Abstract
ABSTRACTReceptor-mediated endocytosis is a cellular process commonly hijacked by viruses to enter cells. The stages of entry are well described for certain viruses, but the host factors that mediate each step are less well characterized. We previously identified endosomal cation channel mucolipin-2 (MCOLN2) as a host factor that promotes viral infection. Here, we assign a role for MCOLN2 in modulating viral entry. We show that MCOLN2 specifically promotes viral vesicular trafficking and subsequent escape from endosomal compartments. This mechanism requires channel activity, occurs independently of antiviral signaling, and broadly applies to enveloped RNA viruses that require transport to late endosomes for infection, including influenza A virus, yellow fever virus, and Zika virus. We further identify a rare allelic variant of human MCOLN2 that has a loss-of-function phenotype with respect to viral enhancement. These findings establish a mechanistic link between an endosomal cation channel and late stages of viral entry.
Highlights
Receptor-mediated endocytosis is a cellular process commonly hijacked by viruses to enter cells
We showed that MCOLN2 enhances infection of viruses from multiple families, including yellow fever virus (YFV) (Flaviviridae), influenza A virus (IAV) (Orthomyxoviridae), and equine arteritis virus (EAV) (Arteriviridae)
MCOLN2 had no effect on Venezuelan equine encephalitis virus (VEEV) (Togaviridae), respiratory syncytial virus (RSV) (Rhabdoviridae), or vesicular stomatitis virus (VSV) (Paramyxoviridae) [2, 3]
Summary
Receptor-mediated endocytosis is a cellular process commonly hijacked by viruses to enter cells. We further identify a rare allelic variant of human MCOLN2 that has a loss-of-function phenotype with respect to viral enhancement These findings establish a mechanistic link between an endosomal cation channel and late stages of viral entry. A growing number of cellular host factors are involved in these diverse viral uptake pathways, including coat proteins (clathrin and caveolin), scission factors (dynamin 2), and regulatory and trafficking factors (Ras, RAC1, CDC42, phosphatidylinositol 3-kinase [PI3K], Rab GTPases, etc.) [1]. MCOLN2 belongs to the transient receptor potential (TRP) protein superfamily, which consists of gated, tetrameric cation channels with diverse physiological functions, in sensory signaling. These proteins share a conserved structure of six transmembrane helices with differing cytoplasmic oriented N- and C-terminal domains. Rinkenberger and Schoggins transient receptor potential mucolipin-like (TRPML) family of proteins are localized predominantly to endosomes, where they have roles in vesicular trafficking, autophagy, and membrane fusion [6, 7]
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