Mammalian hybrid pre-autophagosomal structure HyPAS generates autophagosomes

Kumar, Suresh; Javed, Ruheena; Mudd, Michal H.; Pallikkuth, Sandeep; Lidke, Keith A.; Jain, Ashish; Tangavelou, Karthikeyan; Guðmundsson, Sigurður; Ye, Chunyan; Rusten, Tor Erik; Anonsen, Jan Haug; Lystad, Alf Håkon; Claude-Taupin, Aurore; Simonsen, Anne; Salemi, Michelle; Phinney, Brett S.; Li, Jing; Guo, Lian‐Wang; Bradfute, Steven B.; Timmins, Graham S.; Eskelinen, Eeva‐Liisa; Deretić, Vojo

doi:10.1016/j.cell.2021.10.017

Cited by 67 publications

(65 citation statements)

References 168 publications

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“…To identify the nature of these ATG16L1 puncta, we determined their ultrastructure by correlative light electron microscopy (CLEM). Large ATG16L1 puncta in ATG16L1 FL and ATG16L1 307 expressing ATG16L1 KO cells corresponded to complete autophagosomes and vesicular clusters that have recently been reported to contribute to the formation of pre-autophagic structures 31 (Figure 4a and Supplementary Movies 8 and 9). However, fewer ATG16L1 vesicles were present in ATG16L1 230 and ATG16L1 264 expressing cells (Figure 4b and Supplementary Movies 10 and 11).…”

Section: Function Of Atg16l1 In Starvation-induced Autophagymentioning

confidence: 55%

“…The preference of ATG16L1 to bind highly curved membranes is also re ected by its presence on clusters of small vesicles which are involved in autophagy initiation 31 . We observed similar clusters of ATG16L1 vesicles by CLEM and most of these vesicles possessed diameters that were identical to rim-diameters of membrane cups that we observed in our reconstitutions.…”

Section: Discussionmentioning

confidence: 99%

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Phagophore formation by the autophagy conjugation machinery

Wollert

Mohan

Blanc

et al. 2022

Preprint

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Autophagy is a fundamental cellular recycling pathway that captures cytoplasmic material by a phagophore membrane and delivers it to lysosomes for degradation. Nonselective phagophores are generated at specialized ER-domains termed omegasomes. Mechanistically, this process is not well understood. Here, we reconstituted the formation of phagophores from purified components on supported lipid bilayers and by ectopic induction of nonselective autophagy at the plasma membrane. We found that enzymatic conjugation of LC3B to model membranes induces the formation of phagophore-like membrane cups. LC3B functions as membrane anchor, ensuring a sustained interaction of the E3-like ligase complex ATG12¬–ATG5-ATG16L1 with membranes by forming extended membrane coats. ATG16L1 is the major membrane remodeling factor that induces positive membrane curvature, promotes cup formation and stabilizes the rim of membrane cups. Redirecting WIPI2 to the plasma membrane by expressing WIPI2-CAAX induced the formation of omegasome-like membrane cisternae to which LC3B was conjugated. Membrane cups, identical to those observed in vitro, emerged from these cisternae. ATG16L1 variants that did not induce the formation of cups in vitro also failed to promote cup formation in vivo and inhibited the biogenesis of nonselective autophagosomes in cells. We thus propose that ATG16L1 drives the formation of nonselective phagophores by shaping flat donor membranes into membrane cups.

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Section: Function Of Atg16l1 In Starvation-induced Autophagymentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Phagophore formation by the autophagy conjugation machinery

Wollert

Mohan

Blanc

et al. 2022

Preprint

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“…Nsp6 expression inhibited the formation of a hybrid pre-autophagosomal structure (HyPAS). 196 Moreover, Nsp6 can strongly blocked MAVS (mitochondrial antiviral signaling protein)-induced interferon β production and binds TANK binding kinase1 (TBK1) to suppress interferon regulatory factor 3 (IRF3). 197 , 198 Nsp6 also interacts with the sigma-1 receptor, which is considered an effective candidate host protein for host-based repurposing approaches to treat COVID-19 patients.…”

Section: Nonstructural Proteins Of Sras-cov-2mentioning

confidence: 99%

Structural biology of SARS-CoV-2: open the door for novel therapies

Zheng

Zeng

et al. 2022

Sig Transduct Target Ther

195

149

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Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the causative agent of the pandemic disease COVID-19, which is so far without efficacious treatment. The discovery of therapy reagents for treating COVID-19 are urgently needed, and the structures of the potential drug-target proteins in the viral life cycle are particularly important. SARS-CoV-2, a member of the Orthocoronavirinae subfamily containing the largest RNA genome, encodes 29 proteins including nonstructural, structural and accessory proteins which are involved in viral adsorption, entry and uncoating, nucleic acid replication and transcription, assembly and release, etc. These proteins individually act as a partner of the replication machinery or involved in forming the complexes with host cellular factors to participate in the essential physiological activities. This review summarizes the representative structures and typically potential therapy agents that target SARS-CoV-2 or some critical proteins for viral pathogenesis, providing insights into the mechanisms underlying viral infection, prevention of infection, and treatment. Indeed, these studies open the door for COVID therapies, leading to ways to prevent and treat COVID-19, especially, treatment of the disease caused by the viral variants are imperative.

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“…Moreover, the ER-to-Golgi intermediate compartment (ERGIC) is also a membrane source for autophagosomes, possibly by supplying membrane for the nucleation of the phagophore, a notion that is supported by the observation that ERES undergo a remodeling and associate with ERGIC upon nutrient starvation ( Figure 3 ) [ 47 ]. Recently, it has been shown that cis- Golgi-derived FIP200-positive vesicles and ATG16L1-containing endosomal membranes fuse through a mechanism that depends on STX17, the SERCA2 calcium pump, the calcium-regulated membrane tether E-SYT2 and the ER-localized transmembrane calcium regulator SIGMAR1 [ 48 ]. The resulting compartment is a HyPAS, which is important for autophagy initiation and appears to be key in the recognition of diverse cargoes during selective types of autophagy [ 48 ].…”

Section: Autophagosome Formation Mechanismmentioning

confidence: 99%

“…Recently, it has been shown that cis- Golgi-derived FIP200-positive vesicles and ATG16L1-containing endosomal membranes fuse through a mechanism that depends on STX17, the SERCA2 calcium pump, the calcium-regulated membrane tether E-SYT2 and the ER-localized transmembrane calcium regulator SIGMAR1 [ 48 ]. The resulting compartment is a HyPAS, which is important for autophagy initiation and appears to be key in the recognition of diverse cargoes during selective types of autophagy [ 48 ]. It remains to be understood whether the cis- Golgi-derived FIP200-positive vesicles are in fact the ERGIC-derived vesicles, and whether the HyPAS may correspond to the recycling endosome-derived vesicles that were found to be positive for ATG16L1 and ULK1.…”

Section: Autophagosome Formation Mechanismmentioning

confidence: 99%

Molecular regulation of autophagosome formation

Reggiori

2022

Biochemical Society Transactions

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Macroautophagy, hereafter autophagy, is a degradative process conserved among eukaryotes, which is essential to maintain cellular homeostasis. Defects in autophagy lead to numerous human diseases, including various types of cancer and neurodegenerative disorders. The hallmark of autophagy is the de novo formation of autophagosomes, which are double-membrane vesicles that sequester and deliver cytoplasmic materials to lysosomes/vacuoles for degradation. The mechanism of autophagosome biogenesis entered a molecular era with the identification of autophagy-related (ATG) proteins. Although there are many unanswered questions and aspects that have raised some controversies, enormous advances have been done in our understanding of the process of autophagy in recent years. In this review, we describe the current knowledge about the molecular regulation of autophagosome formation, with a particular focus on budding yeast and mammalian cells.

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Mammalian hybrid pre-autophagosomal structure HyPAS generates autophagosomes

Cited by 67 publications

References 168 publications

Phagophore formation by the autophagy conjugation machinery

Phagophore formation by the autophagy conjugation machinery

Structural biology of SARS-CoV-2: open the door for novel therapies

Molecular regulation of autophagosome formation

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