ER-Phagy: Quality Control and Turnover of Endoplasmic Reticulum

Chino, Haruo; Mizushima, Noboru

doi:10.1016/j.tcb.2020.02.001

Cited by 192 publications

(216 citation statements)

References 114 publications

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“…It has been known that ER-phagy is divided into three categories: macro-ER-phagy, micro-ER-phagy, and chaperone-mediated autophagy (CMA). The former is dependent upon the formation of autophagosome 27,39,40 . As we found that the autophagy cargo proteins RB1CC1 (FIP200) or GABARAP are important for ORF8-mediated MHC-I downregulation, it is possible that an unidentified receptor harboring GABARAP-interacting motif (GIM) or FIP200-interacting region (FIR) play a critical role for this process 27,41,42 .…”

Section: Discussionmentioning

confidence: 99%

“…The trafficking from ER to lysosome is most likely mediated by ER-phagy, which is a kind of selective autophagy and could be divided into three categories: macro-ER-phagy, micro-ER-phagy, and vesicular delivery 27 . Six autophagy cargo receptor proteins bind to and recruit substrates to autophagosomal membranes.…”

Section: Orf8 Mediates Mhc-i Degradation Through An Autophagy-dependementioning

confidence: 99%

“…Six autophagy cargo receptor proteins bind to and recruit substrates to autophagosomal membranes. To examine their possible involvement, these receptors, including FAM134B, RTN3, ATL3, SEC62, CCPG1, or TEX264, were knocked down with siRNAs respectively 27 . However, we did not observe any effect upon MHC-I expression in the presence of ORF8 (Fig.…”

Section: Orf8 Mediates Mhc-i Degradation Through An Autophagy-dependementioning

confidence: 99%

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The ORF8 Protein of SARS-CoV-2 Mediates Immune Evasion through Potently Downregulating MHC-I

Zhang

Chen

et al. 2020

Preprint

188

208

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SARS-CoV-2 infection have caused global pandemic and claimed over 5,000,000 tolls [1][2][3][4] . Although the genetic sequences of their etiologic viruses are of high homology, the clinical and pathological characteristics of COVID-19 significantly differ from SARS 5,6 . Especially, it seems that SARS-CoV-2 undergoes vast replication in vivo without being effectively monitored by anti-viral immunity 7 . Here, we show that the viral protein encoded from open reading frame 8 (ORF8) of SARS-CoV-2, which shares the least homology with SARS-CoV among all the viral proteins, can directly interact with MHC-I molecules and significantly down-regulates their surface expression on various cell types. In contrast, ORF8a and ORF8b of SARS-CoV do not exert this function. In the ORF8-expressing cells, MHC-I molecules are selectively target for lysosomal degradation by an autophagy-dependent mechanism.As a result, CTLs inefficiently eliminate the ORF8-expressing cells. Our results demonstrate that ORF8 protein disrupts antigen presentation and reduces the recognition and the elimination of virus-infected cells by CTLs 8 . Therefore, we suggest that the inhibition of ORF8 function could be a strategy to improve the special immune surveillance and accelerate the eradication of SARS-CoV-2 in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Orf8 Mediates Mhc-i Degradation Through An Autophagy-dependementioning

confidence: 99%

Section: Orf8 Mediates Mhc-i Degradation Through An Autophagy-dependementioning

confidence: 99%

See 1 more Smart Citation

The ORF8 Protein of SARS-CoV-2 Mediates Immune Evasion through Potently Downregulating MHC-I

Zhang

Chen

et al. 2020

Preprint

188

208

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“…he ER is the largest cellular organelle that possesses multiple fundamental functions including protein folding, maturation, and trafficking. To maintain its function, it undergoes continuous turnover by the ubiquitin-proteasome system in a process termed endoplasmic reticulum-associated protein degradation (ERAD) and by a selective form of autophagy termed ER-phagy (Chino & Mizushima, 2020). In ER-phagy, ER fragments are sequestered into autophagosomes which then fuse with lysosomes to degrade their internal content.…”

mentioning

confidence: 99%

Selective autophagy bears bone

Fraiberg

Elazar

2020

The EMBO Journal

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The endoplasmic reticulum (ER) is a dynamic intracellular network responsible for folding and maturation of organellar and secreted proteins. Selective autophagy of ER (ER‐phagy) is emerging as an essential process that maintains proteostasis in the ER and is regulated by growth conditions. In this issue, Cinque et al (2020) show that fibroblast growth factor 18 (FGF18) specifically activates ER‐phagy through a TFEB/TFE‐dependent transcriptional regulation of the ER‐phagy receptor Fam134b, a process essential for bone ossification and skeletal development.

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“…One of the main vacuolar/lysosomal degradation processes is ER-phagy. It has emerged as a major quality 40 control pathway, and defects in ER-phagy is linked to various diseases (Chino and Mizushima, 2020; 41 Hübner and Dikic, 2019;Stolz and Grumati, 2019;Wilkinson, 2019). ER-phagy involves cargo receptors 42 that mediate removal of certain regions of the ER via autophagy.…”

mentioning

confidence: 99%

A cross-kingdom conserved ER-phagy receptor maintains endoplasmic reticulum homeostasis during stress

Stephani

Picchianti

Gajic

et al. 2020

Preprint

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2Eukaryotes have evolved various quality control mechanisms to promote proteostasis in the ER.3 Selective removal of certain ER domains via autophagy (termed as ER-phagy) has emerged as a 4 major quality control mechanism. However, the degree to which ER-phagy is employed by other 5 branches of ER-quality control remains largely elusive. Here, we identify a cytosolic protein, C53, 6 that is specifically recruited to autophagosomes during ER-stress, in both plant and mammalian cells. 7C53 interacts with ATG8 via a distinct binding epitope, featuring a shuffled ATG8 interacting motif 8 (sAIM). C53 senses proteotoxic stress in the ER lumen by forming a tripartite receptor complex with 9 the ER-associated ufmylation ligase UFL1 and its membrane adaptor DDRGK1. The 10 C53/UFL1/DDRGK1 receptor complex is activated by stalled ribosomes and induces the degradation 11 of internal or passenger proteins in the ER. Consistently, the C53 receptor complex and ufmylation 12 mutants are highly susceptible to ER stress. Thus, C53 forms an ancient quality control pathway that 13 bridges selective autophagy with ribosome-associated quality control at the ER. 14 15 65 stress, we performed an immunoprecipitation coupled to mass spectrometry (IP-MS) screen to identify 66 AIM-dependent ATG8 interactions triggered by ER stress. We hypothesized that a synthetic AIM peptide 67 that has higher affinity for ATG8 can outcompete, and thus reveal, AIM-dependent ATG8 interactors. To 68 identify this synthetic peptide, we performed a peptide array analysis that revealed the AIM wt peptide 69 (Figure S1a, b; Table S1). Using isothermal titration calorimetry (ITC), we showed that the AIM wt binds 70 4 ATG8 with nanomolar affinity (KD=~700 nM), in contrast to the AIM mutant peptide (AIM mut), which 71 does not show any binding ( Figure S1c-f) or the low micromolar-range affinities measured for most cargo 72 receptors (Zaffagnini and Martens, 2016). As plants have an expanded set of ATG8 proteins, we first tested 73 if any of the ATG8 isoforms specifically responded to ER stress induced by tunicamycin (Kellner et al., 74 2016). Tunicamycin inhibits glycosylation and leads to proteotoxic stress at the ER (Bernales et al., 2006). 75 Quantification of ATG8 puncta in transgenic seedlings expressing GFP-ATG8A-I revealed that 76 tunicamycin treatment significantly induced all nine ATG8 isoforms (Figure S2). Since all ATG8 isoforms 77 were induced, we chose ATG8A, and performed peptide competition coupled IP-MS analysis (See methods 78 for detailed description). In addition to well-known AIM dependent ATG8 interactors such as ATG4 79 (Autophagy related gene 4) and NBR1 (Neighbour of BRCA1) (Wild et al., 2014), our analyses revealed 80 that the highly conserved cytosolic protein C53 (aliases: CDK5RAP3, LZAP, IC53, HSF-27) is an AIM-81 dependent ATG8 interactor (Figure 1a, Table S2, Figure S3). 83To confirm our IP-MS results, we performed in vitro pull-down experiments. Arabidopsis thaliana (At) 84 C53 specifically interacted with GST-ATG8A, and this interac...

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ER-Phagy: Quality Control and Turnover of Endoplasmic Reticulum

Cited by 192 publications

References 114 publications

The ORF8 Protein of SARS-CoV-2 Mediates Immune Evasion through Potently Downregulating MHC-I

The ORF8 Protein of SARS-CoV-2 Mediates Immune Evasion through Potently Downregulating MHC-I

Selective autophagy bears bone

A cross-kingdom conserved ER-phagy receptor maintains endoplasmic reticulum homeostasis during stress

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