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

PLoS Pathog. 2021 May 27;17(5):e1009599. doi: 10.1371/journal.ppat.1009599. eCollection 2021 May.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • COVID-19 / metabolism
  • Cell Line
  • Chlorocebus aethiops
  • Coronavirus 229E, Human / drug effects*
  • Coronavirus 229E, Human / physiology
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / virology
  • Host Microbial Interactions / genetics
  • Host Microbial Interactions / physiology*
  • Humans
  • Membrane Proteins / metabolism*
  • Membrane Proteins / physiology
  • SARS-CoV-2 / drug effects
  • SARS-CoV-2 / metabolism
  • SARS-CoV-2 / pathogenicity
  • Vero Cells
  • Virus Replication / drug effects


  • Antiviral Agents
  • Membrane Proteins
  • TMEM41B protein, human