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Published on: December 29, 2015
TMEM41B is a pan-flavivirus host factor
H-Heinrich Hoffmann1, William M Schneider1, Kathryn Rozen-Gagnon1
1Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
Abstract:
Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection. Based on our mechanistic studies we hypothesize that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication.
Highlights:
TMEM41B and VMP1 are required for both autophagy and flavivirus infection, however, autophagy is not required for flavivirus infection.TMEM41B associates with viral proteins and likely facilitates membrane remodeling to establish viral RNA replication complexes.TMEM41B single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection.TMEM41B-deficient cells display an exaggerated innate immune response upon high multiplicity flavivirus infection.
Insights
Transmembrane protein 41B (TMEM41B) is essential for flavivirus replication by aiding viral RNA complexes. Specific genetic variations in TMEM41B reduce flavivirus infection rates in East Asian populations.
Area of Science:
- Virology
- Cell Biology
- Genetics
Background:
- Flaviviruses are a significant public health concern, causing regular outbreaks transmitted by mosquitoes and ticks.
- Identifying host factors essential for flavivirus infection is crucial for developing antiviral strategies.
Approach:
- Conducted genome-wide CRISPR-Cas9 loss-of-function screens to identify host genes required for flavivirus replication.
- Focused on characterizing the roles of TMEM41B and VMP1 in the viral replication cycle.
- Performed mechanistic studies to elucidate the function of TMEM41B in virus infection.
Key Points:
- TMEM41B is required for the replication of all tested Flaviviridae family members and also for SARS-CoV-2 (Coronaviridae).
- Single nucleotide polymorphisms (SNPs) in TMEM41B, common in East Asian populations, reduce flavivirus infection.
- TMEM41B appears to be recruited to viral RNA replication complexes, facilitating membrane curvature for genome replication.
Conclusions:
- TMEM41B and VMP1 are necessary for both autophagy and flavivirus infection, though autophagy itself is not required for flavivirus replication.
- TMEM41B interacts with viral proteins and likely remodels membranes to support viral RNA replication complex formation.
- TMEM41B deficiency exacerbates the innate immune response to high-multiplicity flavivirus infection.
