The various shades of ER‐phagy

Stolz, Alexandra

doi:10.1111/febs.15031

Cited by 31 publications

(29 citation statements)

References 47 publications

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“…In mammals, six different receptors have been identified: FAM134B/RETREG1, SEC62, RTN3L, CCPG1, ATL3, and TEX264 (Khaminets et al, 2015;Fumagalli et al, 2016;Grumati et al, 2017;Smith et al, 2018;Chen et al, 2019;Chino et al, 2019). Some of them (FAM134B and RTN3L) are intramembrane proteins characterized by the presence of a specific domain called the reticulon homology domain (RHD), which is essential for their insertion in the ER membrane and ER-phagy regulation (Stolz and Grumati, 2019; Figure 1A).…”

Section: Selective Autophagymentioning

confidence: 99%

Reticulon Homology Domain-Containing Proteins and ER-Phagy

D’Eletto

Oliverio

Sano

2020

Front. Cell Dev. Biol.

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The endoplasmic reticulum (ER) is a dynamic membrane system comprising different and interconnected subdomains. The ER structure changes in response to different stress conditions through the activation of a selective autophagic pathway called ERphagy. This represents a quality control mechanism for ER turnover and component recycling. Several ER-resident proteins have been indicated as receptors for ERphagy; among these, there are proteins characterized by the presence of a reticulon homology domain (RHD). RHD-containing proteins promote ER fragmentation by a mechanism that involves LC3 binding and lysosome delivery. Moreover, the presence of a correct RHD structure is closely related to their capability to regulate ER shape and morphology by curvature induction and membrane remodeling. Deregulation of the ER-selective autophagic pathway due to defects in proteins with RHD has been implicated in several human diseases, infectious and neurodegenerative diseases in particular, as well as in cancer development. While the molecular mechanisms and the physiological role of ER-phagy are not yet fully understood, it is quite clear that this process is involved in different cellular signaling pathways and has an impact in several human pathologies.

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Section: Selective Autophagymentioning

confidence: 99%

Reticulon Homology Domain-Containing Proteins and ER-Phagy

D’Eletto

Oliverio

Sano

2020

Front. Cell Dev. Biol.

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

Section: Introductionmentioning

confidence: 99%

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

Stephani

Picchianti

Gajic

et al. 2020

eLife

173

167

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Eukaryotes have evolved various quality control mechanisms to promote proteostasis in the ER. Selective removal of certain ER domains via autophagy (termed as ER-phagy) has emerged as a major quality control mechanism. However, the degree to which ER-phagy is employed by other branches of ER-quality control remains largely elusive. Here, we identify a cytosolic protein, C53, that is specifically recruited to autophagosomes during ER-stress, in both plant and mammalian cells. C53 interacts with ATG8 via a distinct binding epitope, featuring a shuffled ATG8 interacting motif (sAIM). C53 senses proteotoxic stress in the ER lumen by forming a tripartite receptor complex with the ER-associated ufmylation ligase UFL1 and its membrane adaptor DDRGK1. The C53/UFL1/DDRGK1 receptor complex is activated by stalled ribosomes and induces the degradation of internal or passenger proteins in the ER. Consistently, the C53 receptor complex and ufmylation mutants are highly susceptible to ER stress. Thus, C53 forms an ancient quality control pathway that bridges selective autophagy with ribosome-associated quality control in the ER.

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“…In the absence of infection, macroautophagy, referred to here as autophagy, functions to degrade bulk cytoplasmic contents or damaged organelles by fusion with the lysosome, referred to as autophagic flux (11,12). Autophagy can thus target many aspects of flavivirus infection, including direct clearance of viral particles and clearance of viral replication factories within the ER (13)(14)(15). However, the full relationship between flaviviruses and autophagy remains unclear.…”

mentioning

confidence: 99%

BPIFB3 Regulates Endoplasmic Reticulum Morphology To Facilitate Flavivirus Replication

Evans

Lennemann

Coyne

2020

J Virol

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Flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), rely heavily on the availability of endoplasmic reticulum (ER) membranes throughout their life cycle, and degradation of ER membranes restricts flavivirus replication. Accordingly, DENV and ZIKV restrict ER turnover by protease-mediated cleavage of reticulophagy regulator 1 (RETREG1), also known as FAM134B, an autophagy receptor responsible for targeted ER sheet degradation. Given that the induction of autophagy may play an important role in flavivirus replication, the antiviral role of RETREG1 suggests that specialized autophagic pathways may have differential effects on the flavivirus life cycle. We previously identified BPI fold-containing family B member 3 (BPIFB3) as a regulator of autophagy that negatively controls enterovirus replication. Here, we show that in contrast to enteroviruses, BPIFB3 functions as a positive regulator of DENV and ZIKV infection and that its RNA interference-mediated silencing inhibits the formation of viral replication organelles. Mechanistically, we show that depletion of BPIFB3 enhances RETREG1-dependent reticulophagy, leading to enhanced ER turnover and the suppression of viral replication. Consistent with this, the antiviral effects of BPIFB3 depletion can be reversed by RETREG1 silencing, suggesting a specific role for BPIFB3 in regulating ER turnover. These studies define BPIFB3 as a required host factor for both DENV and ZIKV replication and further contribute to our understanding of the requirements for autophagy during flavivirus infection. IMPORTANCE Flaviviruses and other arthropod-transmitted viruses represent a widespread global health problem, with limited treatment options currently available. Thus, a better understanding of the cellular requirements for their infection is needed. Both DENV and ZIKV rely on expansion of the endoplasmic reticulum (ER) and the induction of autophagy to establish productive infections. However, little is known regarding the interplay between the requirements for autophagy initiation during infection and the mechanisms used by these viruses to avoid clearance through the autophagic pathway. Our study highlights the importance of the host factor BPIFB3 in regulating flavivirus replication and further confirms that the RETREG1-dependent reticulophagy pathway is antiviral to both DENV and ZIKV.

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The various shades of ER‐phagy

Cited by 31 publications

References 47 publications

Reticulon Homology Domain-Containing Proteins and ER-Phagy

Reticulon Homology Domain-Containing Proteins and ER-Phagy

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

BPIFB3 Regulates Endoplasmic Reticulum Morphology To Facilitate Flavivirus Replication

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