Julia Noack

How viruses hijack the ERAD tuning machinery

ABSTRACT An essential step during the intracellular life cycle of many positive-strand RNA viruses is the rearrangement of host cell membranes to generate membrane-bound replication platforms. For example, Nidovirales and Flaviviridae subvert the membrane of the endoplasmic reticulum (ER) for their replication. However, the absence of conventional ER and secretory pathway markers in virus-induced ER-derived membranes has for a long time hampered a thorough understanding of their biogenesis. Recent reports highlight the analogies between mouse hepatitis virus-, equine arteritis virus-, and Japanese encephalitis virus-induced replication platforms and ER-associated degradation (ERAD) tuning vesicles (or EDEMosomes) that display nonlipidated LC3 at their cytosolic face and segregate the ERAD factors EDEM1, OS-9, and SEL1L from the ER lumen. In this Gem, we briefly summarize the current knowledge on ERAD tuning pathways and how they might be hijacked for viral genome replication. As ERAD tuning components, such as SEL1L and nonlipidated LC3, appear to contribute to viral infection, these cellular pathways represent novel candidate drug targets to combat positive-strand RNA viruses.

Unconventional roles of nonlipidated LC3 in ERAD tuning and coronavirus infection

Secretory and membrane proteins attain their native structure in the endoplasmic reticulum (ER). Folding-defective polypeptides are selected for degradation by processes collectively defined as ER-associated degradation (ERAD). Enhanced ERAD activity may interfere with protein biogenesis by inappropriately targeting not-yet-native protein folding intermediates for disposal. The regulation of ERAD is therefore crucial to maintain cellular proteostasis. At steady-state, select ERAD regulators are constitutively removed from the ER in a series of processes collectively defined as ERAD tuning. This sets the ERAD activity at levels that do not interfere with completion of ongoing folding programs. Our latest work highlights a crucial, autophagy-independent role of nonlipidated LC3 (LC3-I) as part of a membrane-bound receptor that insures the vesicle-mediated clearance of at least two ERAD regulators from the ER, EDEM1 and OS9. This pathway is hijacked by coronaviruses (CoV), and silencing of LC3 substantially inhibits viral replication.

Protein trafficking: RESETting proteostasis

A recent study reveals a new cellular pathway that clears the endoplasmic reticulum of misfolded, GPI-anchored proteins at the onset of endoplasmic reticulum (ER) stress. This mechanism, termed rapid ER stress–induced export, represents a nontranscriptional response to mitigate acute ER stress.

Retraction Notice to: Role of the SEL1L:LC3-I Complex as an ERAD Tuning Receptor in the Mammalian ER

(Molecular Cell 46, 809–819; June 29, 2012)This article has been retracted at the request of the authors. The study reported that expression of misfolded proteins in the ER affects the composition of complexes containing EDEM1, SEL1L, and LC3-I, thereby modulating ERAD activity in the absence of UPR induction. During efforts to extend this work, we have been unable to replicate some of the results obtained by the first author of the paper. The authors have now found that Western blot data shown in Figures 1B, 3A, and 4A were inappropriately processed by the first author of the paper, such that they do not accurately report the original data. This could call into question some of our conclusions on how the presence of misfolded proteins might affect assembly and function of the ERAD machinery. The authors therefore wish to immediately retract the paper. The authors’ lab continues working on the regulation of the ERAD machinery aiming to publish verified data in the near future. The authors sincerely apologize for any difficulties that may have been experienced by the scientific community. The first author, R.B., declined to sign the Retraction Notice.

Non-Lipidated LC3 is Essential for Mouse Hepatitis Virus Infection

Abstract Coronaviruses (CoVs) are enveloped viruses responsible for severe respiratory diseases in birds and mammals. In infected cells they induce double-membrane vesicles (DMVs) and convoluted membranes (CMs), which are thought to be the site of virus replication. Until recently, both the origin of the CoV-induced vesicles and the exact localization of CoV replication remained unknown. It was assumed that the vesicles derive from the endoplasmic reticulum (ER). Nevertheless no conventional protein markers of the ER, ER-to-Golgi intermediate compartment (ERGIC), Golgi, or coatomer proteins could be detected in these structures. Recent data from our laboratory and others shed light on this mystery. It appears that the Mouse Hepatitis Virus (MHV), a prototype CoV, co-opts ERAD tuning vesicles as replication platforms. These vesicles are released from the ER, but do not contain conventional ER markers or coatomer proteins. Rather, they contain ERAD factors such as SEL1L, EDEM1, and OS-9 that are constitutively cleared from the folding compartment by so called ERAD tuning programs, and display non-lipidated LC3 (LC3-I) periferically associated at their limiting membrane. In MHV-infected cells, the ERAD tuning vesicle markers co-localize with viral non-structural proteins and double-stranded RNA, which are DMV markers. The unconventional role of LC3-I in the MHV infection cycle is further supported by the fact that Atg5 and Atg7, both essential proteins for LC3-I to LC3-II conversion and macroautophagy, are dispensable for CoV replication and DMV formation. These new insights into CoV replication might lead to new therapies to treat CoV infections. They also reveal a novel role for LC3, in its non-lipidated form, in both maintenance of cellular proteostasis and viral infection, the latter function supported by recent findings showing involvement of LC3-I in equine arteritis virus replication.

Corrigendum: Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery

Nature Cell Biology 18, 1173–1184 (2016); published online 17 October 2016; corrected after print 18 November 2016. In the version of this Article originally published, the name of co-author Eduardo Cebollero Presmanes was coded wrongly resulting in it being incorrect when exported to citation databases.

Correction for Noack et al., How Viruses Hijack the ERAD Tuning Machinery

Reference EPFL-ARTICLE-208271doi:10.1128/Jvi.03670-14View record in Web of Science Record created on 2015-05-29, modified on 2017-05-12

How Viruses Hijack the ERAD Tuning Machinery (vol 88, pg 10272, 2014)

Reference EPFL-ARTICLE-208271doi:10.1128/Jvi.03670-14View record in Web of Science Record created on 2015-05-29, modified on 2017-05-12