TMEM41B is a host factor required for the replication of diverse coronaviruses including SARS-CoV-2.

Joseph D Trimarco,Vineet D Menachery,Clare M Smith,Nicholas S Heaton,Kaitlyn N Burke,Brook E Heaton,Ryan R Chaparian,Raquel A Binder,Gregory C Gray,Benhur Lee

doi:10.1371/journal.ppat.1009599

Abstract

Antiviral therapeutics are a front-line defense against virally induced diseases. Because viruses frequently mutate to escape direct inhibition of viral proteins, there is interest in targeting the host proteins that the virus must co-opt to complete its replication cycle. However, a detailed understanding of the interactions between the virus and the host cell is necessary in order to facilitate development of host-directed therapeutics. As a first step, we performed a genome-wide loss of function screen using the alphacoronavirus HCoV-229E to better define the interactions between coronaviruses and host factors. We report the identification and validation of an ER-resident host protein, TMEM41B, as an essential host factor for not only HCoV-229E but also genetically distinct coronaviruses including the pandemic betacoronavirus SARS-CoV-2. We show that the protein is required at an early, but post-receptor engagement, stage of the viral lifecycle. Further, mechanistic studies revealed that although the protein was not enriched at replication complexes, it likely contributes to viral replication complex formation via mobilization of cholesterol and other lipids to facilitate host membrane expansion and curvature. Continued study of TMEM41B and the development of approaches to prevent its function may lead to broad spectrum anti-coronavirus therapeutics.

Highlights

Human coronaviruses (HCoVs) can cause a spectrum of disease ranging from mild respiratory illness to lethal disease [1]
The COVID-19 pandemic has highlighted the burden that emerging coronaviruses can place on global health systems
While those associated with severe disease and pandemic outbreaks, such as SARS, MERS, and SARS-CoV-2 are beta-coronaviruses, HCoVs that typically cause a mild seasonal respiratory disease such as 229E, NL63, HKU1 and OC43 span both the alpha- and beta-coronavirus genera [4]

Summary

Introduction

Human coronaviruses (HCoVs) can cause a spectrum of disease ranging from mild respiratory illness to lethal disease [1]. The CoVs that cause human disease fall into the alpha- and beta-coronavirus genera. It is likely that even divergent HCoVs require some of the same key host factors as there are many conserved features of their lifecycle such as the reorganization and expansion of membranes to establish sites of replication [6,7]. Identifying these conserved factors and understanding their role in the viral replication cycle may lead to the development of broadly acting antivirals that could be used against current, and potentially even future, coronavirus outbreaks

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