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TMEM41B and VMP1 modulate cellular lipid and energy metabolism for facilitating Dengue virus infection

ABSTRACT: Lipid metabolism is an intricate yet crucial cellular process co-opted by multiple viruses for replication and biogenesis. Transmembrane Protein 41B (TMEM41B) and Vacuole Membrane Protein 1 (VMP1) are two recently identified ER-resident lipid scramblases that play a role in autophagosome formation and cellular lipid metabolism. Importantly, TMEM41B is also a newly validated host dependency factor required for productive infection of several medically important enveloped RNA viruses, such as flaviviruses and human coronaviruses. However, the exact underlying mechanism of TMEM414B in modulating viral infections remains an open question. Here, we uncovered that TMEM41B and VMP1 deficiencies severely impaired replication of flavivirus and human coronavirus via multiple parallel cellular mechanisms. In accordance with previous reports, we validated that both TMEM41B and VMP1 are indispensable for all four serotypes of dengue virus (DENV) and human coronavirus OC43 (HCoV-OC43) to infect human cells, but not chikungunya virus, an alphavirus. Impaired dengue virus replication in TMEM41B and VMP1 deficient cells could induce a robust activation of innate immune RNA sensing as evidenced by hyperactivation of RIG-I and MDA5. However, this phenomenon was a consequence but not the root cause of the diminished viral replication. Notably, the impact of TMEM41B deficiency on DENV replication could be reversed by complementing the cells using exogenous unsaturated fatty acids, indicating a metabolic role for TMEM41B in flavivirus infection. Furthermore, we found that derailed cellular energy metabolism could be a contributing factor to block DENV infection as TMEM41B and VMP1 deficient cells harbored higher levels of compromised mitochondria that exhibited aberrant functions in facilitating beta-oxidation. Using lipidome and metabolome profiling of TMEM41B and VMP1 deficient cells, we further revealed that each of these genetic deficiencies result in distinctive cellular metabolic dysregulations, underlining their necessity for a balanced metabolic landscape, and strengthening the metabolic role of these ER membrane proteins in facilitating virus infection. Our results highlighted that TMEM41B and VMP1 are required for homeostasis of cellular metabolism, and this metabolic role contributes to their essentiality in facilitating DENV infection.

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Cultured Cells

DISEASE(S): Viral Infection

SUBMITTER: Liang Cui

PROVIDER: ST002164 | MetabolomicsWorkbench | Wed May 11 00:00:00 BST 2022

REPOSITORIES: MetabolomicsWorkbench

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TMEM41B and VMP1 modulate cellular lipid and energy metabolism for facilitating Dengue virus infection

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