The retromer and retriever both highly conserved multi-protein complexes and their associated protein complexes facilitate the recycling of transmembrane proteins Cullen and Steinberg, , and TBC1D5 the GAP for Rab7a, see below inhibits the retromer complex.

However, during metabolic stress, TBC1D5 binds to LC3 on autophagosomes; this relieves its inhibition of the retromer, which then associates with endosomal membranes, resulting in the recycling of endocytosed GLUT1 to the PM to facilitate glucose uptake Roy et al.

Furthermore, autophagy maintains endosomal homeostasis through recognition and targeting of damaged EEs. Moreover, loss of autophagy disrupts recycling of epidermal growth factor receptor EGFR to the PM and perturbs EGF-mediated signaling Fraser et al.

The Notch signaling pathway is a key regulator of stem cells and crucial for development of most tissues. The Notch receptor is cleaved after ligand binding; this releases the Notch intracellular domain NICD , which translocates to the nucleus to activate target genes Bray and Bernard, The canonical degradation of the Notch1 receptor is through endocytosis Bray, However, autophagy impacts on Notch signaling through uptake of Notch1 receptor into ATG16L1-containing vesicles, resulting in autophagy-mediated degradation of Notch1 Wu et al.

Here, autophagy impairment in Atg16L1 hypomorph mice results in retarded Notch 1-dependent stem cell differentiation. In addition, p62 can bind to Notch1 intracellular domain NICD1 and promote its autophagic degradation Zhang et al.

Thus, autophagy can also affect the transcriptional activity necessary for Notch1 signaling Zhang et al. Numerous membrane sources are implicated in the formation of autophagosomes Kawabata and Yoshimori, In particular, ATG9A- and ATG16L1-containing membrane vesicles, which are formed by endocytosis, traffic through the endocytic compartment and carry autophagy mediators to sites of autophagosome formation Fig.

Of the two mammalian ATG9 transmembrane protein homologs, ATG9A and ATG9B, ATG9A exhibits the most ubiquitous expression Yamada et al. ATG9A is usually localized in Golgi membranes and endosomes, and undertakes complex trafficking routes that involve both endocytic and secretory pathways Young et al.

ATG9A is routed to the PM and returns through clathrin-dependent endocytosis, traveling through the early endocytic compartment and recycling endosomes. ATG9A interacts with AP2 and, together with the Rab GAP TBC1D5 see below , is required for proper sorting of ATG9A towards sites of autophagosome formation Popovic and Dikic, ATG9A-containing vesicles are mobilized from Rabpositive recycling endosomes Takahashi et al.

During amino acid starvation, ATG9A is found on vesicles and on tubular vesicular structures, termed the ATG9 compartments Itakura et al. ATG9A is involved in supplying lipids and proteins to the phagophore Noda, Fig. Rab1b also localizes to ATG9A-containing vesicles and participates in formation of autophagosomes Kakuta et al.

ATG9A-containing vesicles that originate from the Golgi deliver the Golgi-resident PI4-kinase PI4KIIIβ to the site of autophagosome initiation.

Here, PI4KIIIβ and the resulting PI4P may recruit the ULK1 complex through ATG13 Judith et al. ATG16L1 is essential for the correct localization of the ATG5—ATG12 conjugate to the phagophore Fujita et al.

ATG16L1 is a peripheral membrane protein present on vesicles formed by clathrin-dependent endocytosis. Clathrin heavy chain interacts with the N-terminal region of ATG16L1 Ravikumar et al. ATG16L1-containing vesicles are distinct from those that have ATG9A, and they bypass EEs Fig.

The membrane-curvature-inducing protein annexin A2 enhances formation and homotypic fusion of ATG16L1-positive vesicles preceding their integration into the expanding phagophore Morozova et al.

The homotypic fusion is dependent on the SNARE VAMP7 Moreau et al. ATG16L1-containing vesicles coalesce with those that have ATG9A into Rabpositive recycling endosomes. Here, VAMP3 mediates the fusion event Puri et al. The sorting nexin SNX18 and Rab11 are important for recruitment of ATG16L1 to recycling endosomes Knævelsrud et al.

Furthermore, SNX18 mediates the transport of ATG9A and ATG16L1 from recycling endosomes to the phagophore through interaction with the GTPase dynamin-2 Søreng et al. In addition, the PI3P-binding protein WIPI2b recruits ATG16L1 to the omegasome Dooley et al.

Here, the E3 ubiquitin ligase-like ATG12—ATG5—ATG16L1 complex conjugates ATG8 proteins to PE on the growing phagophore.

However, PI3P is found on both early and late endosomes Gillooly et al. Rab5-positive EEs have been reported to sequester depolarized mitochondria into single-membrane structures Hammerling et al. Furthermore, Rab11a-enriched REs can act as primary platforms for phagophore formation.

Here, co-incidence detection of PI3P and Rab11a by WIPI2 is suggested to mediate autophagosome formation Puri et al. Rab11a-containing REs have also been suggested to be sites of autophagosome formation during viral infection Kuroki et al.

This highlights the possible role of the endosomal system in phagophore formation. ESCRT-mediated ILV formation during endosome maturation resembles the topological membrane transformation involved in phagophore closure Knorr et al.

Indeed, the ESCRT-III component CHMP2A was identified as regulating phagophore closure Takahashi et al. Interestingly, components of ESCRT-I, -II and -III, including VPS4 and the accessory protein ALIX also known as PDCD6IP , are involved in the engulfment of cargo in endosomal microautophagy Tekirdag and Cuervo, Moreover, upon acute amino acid starvation, endosomal microautophagy leads to a selective and rapid degradation of certain autophagy receptors and ATG8 proteins.

The mechanism requires the activities of the ESCRT-III component CHMP4B and VPS4 in late endosomes Mejlvang et al. These examples reveal that complex interconnections and interdependence exist between the endocytic compartment and different forms of autophagy for cargo engulfment and degradation.

Taken together, autophagosome formation appears tightly coupled to components of the endosomal system, not only with regard to the delivery of components and membranes through ATG9A- and ATG16L1-containing vesicles, but also through a role of ESCRT-III in phagophore closure.

Autophagosome maturation involves fusions with different parts of the endolysosomal compartment. Autophagosomes can fuse with early or late endosomes, forming amphisomes Gordon and Seglen, , before fusing with lysosomes.

Autophagosomes also directly fuse with lysosomes Mizushima et al. PI3P is a key player in membrane dynamics and participates in nearly all aspects of endosomal function, as well as in autophagy, including fusion with lysosomes Nascimbeni et al.

PI4P generation on autophagosomes is also critically important for their fusion with lysosomes. GABARAPs bind to and recruit phosphatidylinositol 4-kinase IIα PI4KIIα , a lipid kinase that generates PI4P, to autophagosomes Wang et al. The importance of the endocytic compartment for autophagosome maturation is evident from experiments showing that inhibition of early endosome function Razi et al.

The main fusion machinery consists of Rab GTPases, tethering factors, SNAREs and other auxiliary proteins that govern fusion of the outer autophagosomal membrane with membranes of the endolysosomal system Fig.

Rab GTPases exist in an inactive cytosolic GDP-bound form and a membrane-anchored, active GTP-bound form that subsequently interacts with effector proteins. Guanine nucleotide exchange factors GEFs catalyze GDP dissociation to allow replacement with GTP, while GTPase-activating proteins GAPs mediate hydrolysis of GTP to GDP Zhen and Stenmark, ; Pfeffer, Approximately 60 different Rab isoforms are present in mammals Pfeffer, ATG8s interact with a number of TBC1-domain-containing Rab GAPs involved in endocytosis Popovic et al.

Rab7 is essential for LE trafficking and lysosome biogenesis Bucci et al. Rab7 also has a key role in the maturation of autophagosomes to autolysosomes mediated by fusion events with lysosomes Gutierrez et al.

The Mon1—Ccz1 complex acts as a GEF for Rab7 Kinchen and Ravichandran, ; Gerondopoulos et al. The GAPs that regulate Rab7 are TBC1D2A Armus , TBC1D2B, TBC1D5 and TBC1D15, and they interact with LC3 on autophagosomes Stroupe, A recent analysis of mammalian Rab7-knockout KO cells suggests that Rab7 is involved in autolysosome maturation rather than the fusion step itself Kuchitsu et al.

Furthermore, the Golgi-resident Rab2 is involved in autophagosome maturation by recruiting the homotypic fusion and protein sorting HOPS complex see below Ding et al.

Tethering factors enhance the specificity and efficiency of membrane fusion and are recruited to specific membranes through coordinated binding to Rab proteins, phospholipids, ATG8s and SNAREs Kriegenburg et al. The HOPS complex VPS33A, VPS16, VPS11, VPS18, VPS39 and VPS41 is the core-tethering factor mediating autophagosome—lysosome fusion.

HOPS is recruited to endolysosomal membranes by binding to the Rab7 effectors pleckstrin homology domain containing protein family member 1 PLEKHM1 and Rab7a-interacting lysosomal protein RILP Wijdeven et al. PLEKHM1 binds to ATG8s, preferentially GABARAPs, on autophagosomes and promotes SNARE-complex assembly see below McEwan et al.

HOPS can be recruited to autophagosomes by interacting with the SNARE syntaxin 17 STX17 Jiang et al. The tethering factor EPG5 is localized to the endolysosomal compartment through Rab7 and interacts with autophagosomes via ATG8s and the SNAREs STX17 and synaptosome associated protein 29 SNAP29 to facilitate fusion Wang et al.

ATG14, a component of PI3KC3-C1, can also function as a tethering factor on the nascent autophagosome by interacting with STX17 to stabilize the STX17—SNAP29 complex and promote membrane fusion Diao et al.

Furthermore, ATG14 can interact with GABARAPs through a C-terminal LIR motif Birgisdottir et al. Similar to what is found for EPG5, other tethering factors interact with ATG8s for capturing autophagosomes.

Baculovirus IAP repeat-containing ubiquitin-conjugating enzyme BRUCE , which is present on the endolysosomal compartment, promotes autolysosome formation by interacting with ATG8s as well as STX17—SNAP29 Ebner et al. Finally, tectonin β-propeller repeat containing protein 1 TECPR1 is localized on mature autophagosomes and lysosomes, and has been implicated in tethering by mediating autophagosome fusion with the endocytic system, given that depletion of TECPR1 results in autophagosome accumulation Chen et al.

SNAREs are membrane-anchored proteins that mediate membrane fusion by forming a trans-SNARE complex comprised of a parallel four-helix bundle that contains one R-SNARE helix and three Q-SNARE helices [named after the conserved arginine R and glutamine Q residues, respectively] to bridge the opposing membranes Jahn and Scheller, One is composed of the Q-SNARE STX17 in the autophagosomal membrane bound to the cytosolic Q-SNARE SNAP29 containing two helices , which interacts with either the R-SNARE vesicle associated membrane protein 8 VAMP8 or VAMP7 in the endolysosomal membrane Itakura et al.

The other complex consists of the R-SNARE YKT6 in the autophagosomal membrane, which interacts with SNAP29 bound to the Q-SNARE STX7 in the endolysosomal membrane Matsui et al. Notably, YKT6 can also form a complex with STX17 and SNAP29 that could be involved in the fusion of autophagosomes at different maturation stages.

STX17 and YKT6 are not found on the phagophore and are recruited independently to the autophagosome Matsui et al. STX17 recruitment is accompanied by closure of the nascent autophagosome and allows co-ordination of closure and fusion.

Immunity-related GTPase M IRGM in human cells facilitates efficient targeting of STX17 to autophagosomes through a direct interaction with STX17 and ATG8s via a non-canonical LIR motif. Interestingly, STX17 also interacts with ATG8s through a LIR motif within its SNARE domain Kumar et al.

However, the recruitment of STX17 is not affected by depletion of all the ATG8s Nguyen et al. An unanticipated early role for STX17 in autophagy is that phosphorylation of its serine by TBK1 controls the formation of the mammalian pre-autophagosomal structure mPAS in response to induction of autophagy Kumar et al.

The motifs responsible for the recruitment of SNAREs to membranes must be exposed to allow the assembly of trans-SNARE complexes. SNAP29 engages in SNARE complex formation through interaction with membrane-bound STX17 or STX7 Hohenstein and Roche, ; Diao et al.

Similarly, phosphatidylinositol-binding clathrin assembly protein PICALM regulates the endocytosis of SNAREs, such as VAMP2, VAMP3 and VAMP8, thereby affecting autophagy at different stages Moreau et al.

After fusion is completed, the individual SNARE molecules are released from their complex by the enzyme N -ethylmaleimide sensitive factor NSF and its adaptor soluble NSF-attachment protein α αSNAP Baker and Hughson, Interestingly, GABARAP interacts with NSF Kittler et al.

In addition to STX17 Kumar et al. STX16 is also important for lysosomal biogenesis, and ATG8s regulate its localization to endosomal and lysosomal compartments Gu et al.

Thus, it is becoming increasingly clear that ATG8s serve important roles in autophagy and beyond as membrane scaffolds Johansen and Lamark, Autophagosomes are typically formed throughout the cytoplasm Jahreiss et al. Motor proteins mediate bidirectional transport of autophagosomes and lysosomes between the center and periphery of the cell along microtubules Fig.

The minus-end-directed dynein—dynactin motor complex transports its cargoes to the perinuclear region, whereas plus-end-directed kinesin motor proteins mediate transport towards the cell periphery Gennerich and Vale, Rab GTPases and their effectors govern interactions with motor proteins.

Each Rab regulates a specific step of vesicular trafficking. Rab7 controls transport of autophagosomes, late endosomes and lysosomes Guerra and Bucci, Their minus-end-directed transport towards the cell center is regulated by a complex of Rab7, RILP, the cholesterol sensor oxysterol-binding protein-related protein 1 ORP1L, also known as OSBPL1A and dynein—dynactin Rocha et al.

ORP1L is located on LEs, lysosomes, amphisomes and autolysosomes, where cholesterol levels dictate its ability to engage in complex formation. At low cholesterol levels, ORP1L interacts with an ER membrane protein; this suppresses the interaction of the motor with the Rab7—RILP complex, resulting in vesicle retention in the cell periphery Rocha et al.

Rab7 can also facilitate plus-end-directed transport of autophagosomes and LEs through its effector FYVE and coiled-coil CC domain-containing protein FYCO1 , which binds to LC3 and PI3P on autophagosomes Pankiv et al. In the presence of amino acids, FYCO1-mediated transport of lysosomes towards the cell periphery promotes mTORC1 signaling and suppresses autophagy Hong et al.

The JNK-interacting motor scaffolding protein JIP1 also known as MAPK8IP1 directs both plus-end and minus-end transport of autophagosomes in neurons. JIP1 binds to LC3 via a LIR motif to promote a switch to JIP1-mediated transport of autophagosomes to the perinuclear region for their efficient fusion with lysosomes Fu et al.

The multi-subunit protein complex BLOCrelated complex BORC interacts with the small GTPase ADP-ribosylation factor-like protein 8 ARL8; there are ARL8A and ARL8B forms in mammals on lysosomes.

This promotes ARL8-dependent association with kinesin-5 proteins and lysosome movement towards the cell periphery Pu et al. The BORC—ARL8 interaction is inhibited by low levels of amino acids, resulting in the perinuclear accumulation of lysosomes Filipek et al.

Knockout of BORC subunits causes accumulation of lysosomes in the perinuclear area without affecting basal mTORC1 activity see Box 2 ; this decreases encounters between peripheral autophagosomes and lysosomes resulting in inhibition of autophagic flux. Furthermore, depletion of BORC impairs fusion of autophagosomes with lysosomes, likely due to a lack of BORC-mediated ARL8-dependent recruitment of the HOPS complex to lysosomes Jia et al.

This way, the movement of both autophagosomes and lysosomes affects their fusion rate and the recruitment of tethering factors. Thus, motor protein-mediated trafficking constitutes a crucial part of the encounter and fusion between autophagosomes and lysosomes.

Vesicle trafficking, lysosome reformation and quality control. The motor proteins kinesin and dynein—dynactin are responsible for vesicle transport on microtubules towards the cell periphery plus-end transport and the perinuclear region minus-end transport , respectively.

Rab7 interacts with its effectors FYCO1 and RILP to promote motor-mediated vesicle movements in opposite directions. FYCO1 can also bind to LC3 on the autophagosome membrane. The motor scaffolding protein JIP1 interacts with LC3 on autophagosomes and promotes their perinuclear transport via dynein-dynactin in neurons.

B Autophagic lysosome reformation ALR. A clathrin-coated bud on the surface of an autolysosome acts as the site of tubule generation for lysosome reformation. The tubule is extended through kinesin activity, which provides a pulling force along the microtubule. The GTPase dynamin 2 is responsible for vesicle scission at the tip of the tubule, giving rise to a protolysosome that subsequently matures into a functional lysosome.

C Lysosome damage, repair and removal. Damage of lysosomes in the form of small perforations is recognized by cytosolic galectins that act as damage sensors; such a limited damage triggers the recruitment of the ESCRT machinery for membrane resealing and repair.

Upon more extensive lysosomal membrane damage, the autophagy machinery is recruited by galectins; this removes damaged lysosomes in a process termed lysophagy. In addition to its major role in cellular catabolism, the lysosome has a central role as a nutrient-sensing and metabolic signal-transduction platform Box 2.

Quality control of the lysosome is crucial for propagation of autophagy and endocytosis, and as discussed below, the machinery governing both pathways is involved in lysosome homeostasis. Reformation of lysosomes from endolysosomes and autolysosomes maintains lysosome homeostasis by restoring the level of free lysosomes.

However, the mechanistic details are not well known. In autophagic lysosome reformation ALR , which is crucial for maintaining autophagic flux, functional lysosomes are regenerated from autolysosomes.

During ALR, long tubular structures extend from the autolysosome and small proto-lysosomes bud from the tips of the tubules.

Proto-lysosomes are initially pH neutral and mature into functional lysosomes Fig. Essential factors of ALR are clathrin, PI 4,5 P2-related kinase PIP5K1B and the kinesin motor heavy chain KIF5B Chen and Yu, PIP5K1B converts PI4P into PI 4,5 P2, and AP2 recruits clathrin to PI 4,5 P2 on the autolysosomal membrane, resulting in clathrin-coated buds on the surface Rong et al.

These buds serve as sites of tubule generation with KIF5B providing a pulling force along the microtubules Du et al. Tubule generation is regulated by mTORC1 in an unknown manner Yu et al.

The large GTPase dynamin 2 is responsible for scission at the tip of the tubules, which mediates proto-lysosome formation Fig. The phospholipids PI4P, PI 4,5 P2 and PI3P play important roles as signals and adaptors during this process.

PI3P, which is generated by the active PI3KC3-C2 complex, is important for the scission step Chen and Yu, ; Munson et al.

Many unanswered questions remain regarding ALR, but it is clear that the underlying mechanisms rely on many molecular components important for both endocytosis and autophagy. Damage or rupture of lysosomes occur incidentally, caused by their transported or accumulated cargo, or intentionally through incoming pathogens.

Furthermore, lysosomal membrane permeabilization can elicit cell death pathways Wang et al. Lysosomal damage thus has detrimental consequences for the cell, and protective mechanisms are activated to maintain and restore lysosomal membrane integrity. Recent studies implicate the ESCRT machinery in membrane repair during limited damage of the lysosomal membrane Fig.

These findings demonstrate a dual role of the ESCRT machinery in the endolysosomal compartment, as it is important for sorting of cargo into intraluminal vesicles targeted for degradation and ensuring the integrity of lysosomes in order to maintain biochemical activity. Upon lysosomal membrane damage, luminal glycosylated proteins are exposed as a mark of injured organelles Aits et al.

Severely damaged lysosomes are subsequently removed and recycled by selective autophagy termed lysophagy Hung et al. A group of cytosolic galectins galectin-1, -3, -8 and -9 acts as a specific sensor of lysosomal damage by binding to the exposed glycosylated proteins Thurston et al.

In addition, galectin-8 and galectin-9 can promote autophagy by inhibition of mTORC1 and activation of AMP-activated protein kinase AMPK , respectively Jia et al.

In lysophagy, damaged lysosomes, as well as membrane remnants originating from complete lysosome rupture are engulfed by autophagosomes Papadopoulos and Meyer, Very recently, it has been reported that galectins-3, -8 and -9 coordinate a repair, removal and replacement program for damaged lysosomes.

Here, galectin-3 recruits ESCRT components for repair of lysosomal membranes. When ESCRT-mediated lysosome repair fails, galectin-3 recruits TRIM16 for removal of unsalvageable lysosomes by autophagy, aided by the autophagy-inducing effects of galectin-8 and galectin-9 Jia et al.

In this way, components of the endosomal system and the autophagy machinery are instrumental for the homeostasis of lysosomes.

Autophagy and endocytosis mediate the degradation and recycling of intracellular and extracellular components, respectively. Both pathways involve the gradual maturation and fusions of vesicles, which traffic to their final destination, the lysosome.

The emerging extensive crosstalk between these two pathways is therefore not surprising. Many questions regarding the identity and composition of various intracellular membrane compartments, as well as differential control of their intersections and the protein complexes involved still remain unanswered.

Novel high-resolution live-cell imaging approaches combined with proteomics and CRISPR-based screens will undoubtedly provide further insight. Elucidation of the dynamic interplay between autophagy and endocytosis in the regulation of cell signaling is likely to provide exciting avenues for development of new therapeutic approaches.

We thank members of the Molecular Cancer Research Group for important discussions and Trond Lamark for critical reading of the manuscript. Research in T. is supported by a grant from the Northern Norway Regional Health Authority Helse Nord RHF; grant number HNF We are now welcoming submissions for our upcoming Special Issue: Imaging Cell Architecture and Dynamics.

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Skip Nav Destination Close navigation menu Article navigation. Volume , Issue Previous Article Next Article. Article contents. Overview of the autophagy pathway. Overview of endocytosis. Impact of autophagy on endocytosis and signaling. Autophagosome formation and its intersection with the endosomal system.

Autophagosome maturation is dependent on fusion with the endolysosomal system. Vesicle transport governs fusion between autophagosomes and the endolysosomal system.

Lysosome quality control. Conclusions and perspectives. Article Navigation. REVIEW 22 May Autophagy and endocytosis — interconnections and interdependencies In collection: Autophagy , Membrane Trafficking. Birgisdottir birgisdottir uit. no ; terje.

johansen uit. This site. Google Scholar. Terje Johansen Author and article information. Competing interests The authors declare no competing or financial interests. Online ISSN: Norges Forskningsråd Kreftforeningen Helse Nord RHF HNF Published by The Company of Biologists Ltd.

J Cell Sci 10 : jcs Cite Icon Cite. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. View large Download slide. Table 1. View Large. Box 1. LC3-associated phagocytosis and LAP-like processes.

Box 2. Nutrient sensing and mTORC1 regulation to maintain lysosome homeostasis and autophagic flux. Funding Research in T.

Search ADS. Sensitive detection of lysosomal membrane permeabilization by lysosomal galectin puncta assay. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum.

Architecture and dynamics of the autophagic phosphatidylinositol 3-kinase complex. Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs.

Endolysosomes are the principal intracellular sites of acid hydrolase activity. Beyond self-eating: the control of nonautophagic functions and signaling pathways by autophagy-related proteins.

TRIMs and galectins globally cooperate and TRIM16 and galectin-3 co-direct autophagy in endomembrane damage homeostasis. A mammalian autophagosome maturation mechanism mediated by TECPR1 and the AtgAtg5 conjugate. Pacer mediates the function of class III PI3K and HOPS complexes in autophagosome maturation by engaging Stx Cellular functions and molecular mechanisms of the ESCRT membrane-scission machinery.

Identification of an adaptor-associated kinase, AAK1, as a regulator of clathrin-mediated endocytosis. To degrade or not to degrade: mechanisms and significance of endocytic recycling.

De Duve. ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. RAB2 regulates the formation of autophagosome and autolysosome in mammalian cells.

WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting AtgL1. The WD40 domain of ATG16L1 is required for its non-canonical role in lipidation of LC3 at single membranes. Targeting of early endosomes by autophagy facilitates EGFR recycling and signalling.

LC3 binding to the scaffolding protein JIP1 regulates processive dynein-driven transport of autophagosomes. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy.

A syntaxin SNARE complex distinguishes two distinct transport routes from endosomes to the trans-Golgi in human cells. Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells. Mammalian Atg8 proteins regulate lysosome and autolysosome biogenesis through SNAREs.

Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance. LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer's disease.

A novel AAK1 splice variant functions at multiple steps of the endocytic pathway. LC3-associated phagocytosis - the highway to hell for phagocytosed microbes. Nutrient-dependent mTORC1 association with the ULK1-AtgFIP complex required for autophagy.

Spatiotemporally controlled induction of autophagy-mediated lysosome turnover. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG.

Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy.

Pharmacological modulators of autophagy activate a parallel noncanonical pathway driving unconventional LC3 lipidation. The itinerary of autophagosomes: from peripheral formation to kiss-and-run fusion with lysosomes.

Starvation-induced MTMR13 and RAB21 activity regulates VAMP8 to promote autophagosome-lysosome fusion. Galectin-3 coordinates a cellular system for lysosomal repair and removal. Vesicular stomatitis virus is believed to be taken up by the autophagosome from the cytosol and translocated to the endosomes where detection takes place by a pattern recognition receptor called toll-like receptor 7 , detecting single stranded RNA.

Following activation of the toll-like receptor, intracellular signaling cascades are initiated, leading to induction of interferon and other antiviral cytokines.

A subset of viruses and bacteria subvert the autophagic pathway to promote their own replication. When galectin-8 binds to a damaged vacuole , it recruits an autophagy adaptor such as NDP52 leading to the formation of an autophagosome and bacterial degradation.

Autophagy degrades damaged organelles, cell membranes and proteins, and insufficient autophagy is thought to be one of the main reasons for the accumulation of damaged cells and aging. One of the mechanisms of programmed cell death PCD is associated with the appearance of autophagosomes and depends on autophagy proteins.

This form of cell death most likely corresponds to a process that has been morphologically defined as autophagic PCD. One question that constantly arises, however, is whether autophagic activity in dying cells is the cause of death or is actually an attempt to prevent it.

Morphological and histochemical studies have not so far proved a causative relationship between the autophagic process and cell death.

In fact, there have recently been strong arguments that autophagic activity in dying cells might actually be a survival mechanism. Autophagy is essential for basal homeostasis ; it is also extremely important in maintaining muscle homeostasis during physical exercise.

A study of mice shows that autophagy is important for the ever-changing demands of their nutritional and energy needs, particularly through the metabolic pathways of protein catabolism. In a study conducted by the University of Texas Southwestern Medical Center in Dallas , mutant mice with a knock-in mutation of BCL2 phosphorylation sites to produce progeny that showed normal levels of basal autophagy yet were deficient in stress-induced autophagy were tested to challenge this theory.

Results showed that when compared to a control group, these mice illustrated a decrease in endurance and an altered glucose metabolism during acute exercise. Another study demonstrated that skeletal muscle fibers of collagen VI in knockout mice showed signs of degeneration due to an insufficiency of autophagy which led to an accumulation of damaged mitochondria and excessive cell death.

Both studies demonstrate that autophagy induction may contribute to the beneficial metabolic effects of exercise and that it is essential in the maintaining of muscle homeostasis during exercise, particularly in collagen VI fibers.

Work at the Institute for Cell Biology, University of Bonn, showed that a certain type of autophagy, i. chaperone-assisted selective autophagy CASA , is induced in contracting muscles and is required for maintaining the muscle sarcomere under mechanical tension.

This is necessary for maintaining muscle activity. Because autophagy decreases with age and age is a major risk factor for osteoarthritis , the role of autophagy in the development of this disease is suggested. Proteins involved in autophagy are reduced with age in both human and mouse articular cartilage.

Cancer often occurs when several different pathways that regulate cell differentiation are disturbed. Autophagy plays an important role in cancer — both in protecting against cancer as well as potentially contributing to the growth of cancer.

The role of autophagy in cancer is one that has been highly researched and reviewed. There is evidence that emphasizes the role of autophagy as both a tumor suppressor and a factor in tumor cell survival. Recent research has shown, however, that autophagy is more likely to be used as a tumor suppressor according to several models.

Several experiments have been done with mice and varying Beclin1, a protein that regulates autophagy. In support of the possibility that Beclin1 affects cancer development through an autophagy-independent pathway is the fact that core autophagy factors which are not known to affect other cellular processes and are definitely not known to affect cell proliferation and cell death, such as Atg7 or Atg5, show a much different phenotype when the respective gene is knocked out, which does not include tumor formation.

In addition, full knockout of Beclin1 is embryonic lethal whereas knockout of Atg7 or Atg5 is not. Necrosis and chronic inflammation also has been shown to be limited through autophagy which helps protect against the formation of tumor cells.

Cells that undergo an extreme amount of stress experience cell death either through apoptosis or necrosis. Prolonged autophagy activation leads to a high turnover rate of proteins and organelles.

A high rate above the survival threshold may kill cancer cells with a high apoptotic threshold. Alternatively, autophagy has also been shown to play a large role in tumor cell survival.

In cancerous cells, autophagy is used as a way to deal with stress on the cell. These metabolic stresses include hypoxia, nutrient deprivation, and an increase in proliferation.

These stresses activate autophagy in order to recycle ATP and maintain survival of the cancerous cells. By inhibiting autophagy genes in these tumors cells, regression of the tumor and extended survival of the organs affected by the tumors were found. Furthermore, inhibition of autophagy has also been shown to enhance the effectiveness of anticancer therapies.

New developments in research have found that targeted autophagy may be a viable therapeutic solution in fighting cancer.

As discussed above, autophagy plays both a role in tumor suppression and tumor cell survival. Thus, the qualities of autophagy can be used as a strategy for cancer prevention.

The first strategy is to induce autophagy and enhance its tumor suppression attributes. The second strategy is to inhibit autophagy and thus induce apoptosis. The first strategy has been tested by looking at dose-response anti-tumor effects during autophagy-induced therapies.

These therapies have shown that autophagy increases in a dose-dependent manner. This is directly related to the growth of cancer cells in a dose-dependent manner as well. Secondly, inhibiting the protein pathways directly known to induce autophagy may also serve as an anticancer therapy.

The second strategy is based on the idea that autophagy is a protein degradation system used to maintain homeostasis and the findings that inhibition of autophagy often leads to apoptosis. Inhibition of autophagy is riskier as it may lead to cell survival instead of the desired cell death.

Negative regulators of autophagy, such as mTOR , cFLIP , EGFR , GAPR-1 , and Rubicon are orchestrated to function within different stages of the autophagy cascade. The end-products of autophagic digestion may also serve as a negative-feedback regulatory mechanism to stop prolonged activity.

Regulators of autophagy control regulators of inflammation, and vice versa. Parkinson's disease is a neurodegenerative disorder partially caused by the cell death of brain and brain stem cells in many nuclei like the substantia nigra. Parkinson's disease is characterized by inclusions of a protein called alpha-synuclien Lewy bodies in affected neurons that cells cannot break down.

Deregulation of the autophagy pathway and mutation of alleles regulating autophagy are believed to cause neurodegenerative diseases. Mutations of synuclein alleles lead to lysosome pH increase and hydrolase inhibition. As a result, lysosomes degradative capacity is decreased.

There are several genetic mutations implicated in the disease, including loss of function PINK1 [] and Parkin. Mitochondria is involved in Parkinson's disease. In idiopathic Parkinson's disease, the disease is commonly caused by dysfunctional mitochondria, cellular oxidative stress, autophagic alterations and the aggregation of proteins.

These can lead to mitochondrial swelling and depolarization. Excessive activity of the crinophagy form of autophagy in the insulin-producing beta cells of the pancreas could reduce the quantity of insulin available for secretion, leading to type 2 diabetes.

Since dysregulation of autophagy is involved in the pathogenesis of a broad range of diseases, great efforts are invested to identify and characterize small synthetic or natural molecules that can regulate it.

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Wikimedia Commons. Cellular catabolic process in which cells digest parts of their own cytoplasm. Not to be confused with Autophagia. This article is about the cellular process.

For other uses, see Autophagy disambiguation. Apoptosis — Programmed cell death in multicellular organisms Autophagy database Autophagin — Protease Pages displaying short descriptions with no spaces Mitophagy — autophagic process in which mitochondria are delivered to the vacuole and degraded Pages displaying wikidata descriptions as a fallback Residual body — vesicles containing indigestible materials, part of lysosomal digestion Pages displaying wikidata descriptions as a fallback Sub-lethal damage — Damaging changes to a biological cell Pages displaying short descriptions of redirect targets.

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