Phosphoinositide 3′-Kinase γ Facilitates Polyomavirus Infection

Abstract

Polyomaviruses are small, non-enveloped DNA tumor viruses that cause serious disease in immunosuppressed people, including progressive multifocal leukoencephalopathy (PML) in patients infected with JC polyomavirus, but the molecular events mediating polyomavirus entry are poorly understood. Through genetic knockdown approaches, we identified phosphoinositide 3′-kinase γ (PI3Kγ) and its regulatory subunit PIK3R5 as cellular proteins that facilitate infection of human SVG-A glial cells by JCPyV. PI3Kα appears less important for polyomavirus infection than PI3Kγ. CRISPR/Cas9-mediated knockout of PIK3R5 or PI3Kγ inhibited infection by authentic JCPyV and by JC pseudovirus. PI3Kγ knockout also inhibited infection by BK and Merkel Cell pseudoviruses, other pathogenic human polyomaviruses, and SV40, an important model polyomavirus. Reintroduction of the wild-type PI3Kγ gene into the PI3Kγ knock-out SVG-A cells rescued the JCPyV infection defect. Disruption of the PI3Kγ pathway did not block binding of JCPyV to cells or virus internalization, implying that PI3Kγ facilitates some intracellular step(s) of infection. These results imply that agents that inhibit PI3Kγ signaling may have a role in managing polyomavirus infections.

The Oncogenic Roles of JC Virus T Antigen in Breast Carcinogenesis

“… Nukuzuma et al (2016) found the suppressive effect of topoisomerase I inhibitors topotecan and β-lapachone on JCV propagation in human neuroblastoma cells. Adipocyte plasma membrane protein, PI3Kγ, and its regulatory subunit PIK3R5 promoted JCV infection in human glial cells ( Clark et al, 2020 ; Haley et al, 2020 ). Uleri et al (2011) showed that alternative splicing factor, SF2/ASF, negatively regulated transcription and splicing of JCV genes in glial cells.…”

PI3K/AKT/mTOR Signaling Pathway Is Required for JCPyV Infection in Primary Astrocytes

“…In addition to the PI3K/AKT/mTOR signaling pathway implicated in JCPyV infection [48,50,59], the mitogen-activated protein kinase, extracellular signal-regulated kinase (MAPK/ERK) pathway is required for JCPyV infection [61,73,74]. This pathway is temporally regulated, specifically being phosphorylated upon JCPyV infection, and infection of immortalized cells is significantly reduced when cells are treated with ERK siRNAs or inhibitors [61,66,73,74].…”

“…Previous research has demonstrated that the PI3K/AKT signaling pathway, specifically the AKT and PI3Kγ steps, is required for JCPyV infection in SVGAs and an oligodendrocyte cell line [48,59,82]. To determine if this pathway is implicated in JCPyV infection in NHAs, RNA-seq data was analyzed [66] over the course of JCPyV infection in NHAs and SVGAs.…”

“…In relation to this, our understanding of the AKT signaling pathway during JCPyV infection is limited. Currently, it has been shown that a component of the AKT pathway, specifically phosphoinositide 3-kinase γ (PI3Kγ), is involved in JCPyV infection in cells immortalized with SV40 T Ag, such as SVGAs; the authors hypothesize that this pathway was activated upon stimulation of G protein-coupled receptors (GPCRs) [48]. However, PI3K signaling is complex and is activated by various mechanisms, including Ras, a component of the mitogen-activated protein kinase (MAPK) pathway, and has numerous isoforms defined by their catalytic and regulatory subunits [49].…”

“…Additionally, genes downstream of AKT, such as mechanistic target of rapamycin (mTOR), have also been implicated in JCPyV infection [50]. Overall, these experiments demonstrated the importance of PI3Kγ and mTOR [48,50], but due to the consequences of immortalization, additional research should elucidate these proteins in a primary cell line.…”