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Review
, 218 (3), 757-770

Autophagosome Maturation: An Epic Journey From the ER to Lysosomes

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Review

Autophagosome Maturation: An Epic Journey From the ER to Lysosomes

Yan G Zhao et al. J Cell Biol.

Abstract

Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane autophagosome and their delivery to lysosomes for degradation. In multicellular organisms, nascent autophagosomes fuse with vesicles originating from endolysosomal compartments before forming degradative autolysosomes, a process known as autophagosome maturation. ATG8 family members, tethering factors, Rab GTPases, and SNARE proteins act coordinately to mediate fusion of autophagosomes with endolysosomal vesicles. The machinery mediating autophagosome maturation is under spatiotemporal control and provides regulatory nodes to integrate nutrient availability with autophagy activity. Dysfunction of autophagosome maturation is associated with various human diseases, including neurodegenerative diseases, Vici syndrome, cancer, and lysosomal storage disorders. Understanding the molecular mechanisms underlying autophagosome maturation will provide new insights into the pathogenesis and treatment of these diseases.

Figures

Figure 1.
Figure 1.
Overview of the autophagy pathway. Autophagosomes are generated at PI(3)P-enriched subdomains of the ER, called omegasomes (Ω). A cup-shaped autophagosomal precursor structure, the IM, forms in close association with the omegasome. Upon closure of the IM, cytoplasmic contents are enclosed in double-membrane autophagosomes, also known as AVi. Autophagosomes undergo a series of fusion processes with various endolysosomal compartments, including the earliest vesicular endocytic vesicles (EVE), early endosomes (EE), MVBs, and LEs/lysosomes to form amphisomes, also known as AVi/d. Amphisomes finally mature into functional autolysosomes, also called AVd.
Figure 2.
Figure 2.
SNAREs, tethers, and Rab proteins act in concert to mediate autophagosome–lysosome fusion. (A) Fusion of autophagosomes with LEs/lysosomes requires the concerted actions of SNARE proteins, Rab GTPases, and tethering factors. Amphisomes, which are single and membrane bound, also undergo fusion with LEs/lysosomes. (B) Two sets of cognate SNARE complexes (the autophagosomal STX17 [Qa]-SNAP29[Qbc]-endolysosomal VAMP7/8 [R] complex and the lysosomal STX7 [Qa]-SNAP29-endolysosomal YKT6 [R] complex) function in parallel with each other to mediate autophagosome–LE/lysosome fusion. ATG14 interacts with STX17 and promotes and stabilizes the assembly of the STX17 and SNAP29 complex. (C) Tethering proteins, including EPG5, HOPS, and PLEKHM1, simultaneously bind to ATG8s on autophagosomes and Rab7 on LEs/lysosomes to tether the autophagosomes/amphisomes with LEs/lysosomes for fusion. GRASP55 binds to Atg8s and LAMP2 on lysosomes. Lysosomal-localized BRUCE tethers autophagosomes through interaction with both ATG8s and STX17. HOPS has also been shown to target to autophagosomes via the Mon1-Ccz1-Rab7 module to promote autophagosome maturation. Rab7 is cycled between inactive GDP forms and active GTP forms by the Mon1-Ccz1 complex and the GAP protein Armus, respectively, during autophagosome maturation.
Figure 3.
Figure 3.
Lysosome positioning modulates autophagosome–lysosome fusion efficiency. Center: Amphisome- and lysosome-localized ORP1L senses cholesterol levels. Under adequate cholesterol conditions, ORP1L binds to cholesterol on the membrane through its ORD domain, which further binds to Rab7/RILP for subsequent recruitment of PLEKHM1 and HOPS to facilitate autophagosome–endolysosome fusion. ORP1L also promotes the centripetal movement of amphisomes/autolysosomes through RILP-mediated recruitment of the motor protein dynein. Top: Under low-cholesterol conditions, the interaction of ORP1L with the ER protein VAPA tethers AVs to the ER, which inhibits dynein-mediated centripetal transport and also impairs autophagosome–lysosome fusion by reducing the recruitment of tether proteins. Bottom: The BORC complex increases the ARL8-dependent interaction with kinesins, leading to the centrifugal movement of lysosomes to the cell periphery for efficient fusion with autophagosomes. BORC also facilitates the fusion process by recruiting HOPS and promoting assembly of the STX17-SNAP29-VAMP8 SNAREs. PM, plasma membrane.
Figure 4.
Figure 4.
Nutrient status regulates autophagosome maturation through multiple mechanisms. Starvation decreases O-GlcNAcylation of SNAP29 and promotes its interaction with STX17 and VAMP8 to form trans-SNARE complexes for autophagosome–LE/lysosome fusion. Starvation-induced de-O-GlcNAcylation of GRASP55 causes its translocation to autophagosomes. De-O-GlcNAcylated GRASP55 simultaneously binds to LC3 and LAMP2 to facilitate autophagosome maturation. Inhibition of mTORC1 activity by starvation leads to dephosphorylation of UVRAG, which releases Rubicon and subsequently recruits HOPS to promote autophagosome fusion. The transcription of a network of genes involved in autophagosome–lysosome fusion is activated by the transcription factor TFEB and inhibited by the transcriptional repressor ZKSCAN3. Starvation triggers dephosphorylation of TFEB, resulting in its nuclear translocation. The translocation of ZKSCAN3 out of the nucleus is also promoted by nutrient deficiency.

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