CD2‐Associated Protein Contributes to Hepatitis C, Virus Propagation and Steatosis by Disrupting Insulin Signaling

Abstract

Chronic hepatitis C virus (HCV) infection can result in steatosis, a condition displaying aberrant accumulation of neutral lipid vesicles, the component of lipid droplets (LDs), which are essential for HCV assembly. However, the interplay between HCV infection and steatosis remains unclear. Here, we show that HCV‐infected cells have higher levels of CD2‐associated protein (CD2AP), which plays two distinct, yet tightly linked, roles in HCV pathogenesis: Elevated CD2AP binds to nonstructural protein 5A (NS5A) and participates in the transport of NS5A to LDs to facilitate viral assembly; Up‐regulated CD2AP also interacts with casitas B‐lineage lymphoma (b) (Cbl/Cbl‐b) E3 ligases to degrade insulin receptor substrate 1 (IRS1), which, in turn, disrupts insulin signaling and increases LD accumulation through the IRS1/protein kinase B (Akt)/adenosine monophosphate‐activated protein kinase (AMPK)/hormone‐sensitive lipase (HSL) signaling axis to accommodate viral assembly. In the HCV‐infected mouse model, CD2AP expression is up‐regulated during the chronic infection stage and this up‐regulation correlates well with liver steatosis. Importantly, CD2AP up‐regulation was also detected in HCV‐infected human liver biopsies showing steatosis compared to non‐HCV‐infected controls. Conclusion: CD2AP is indicated as a protein up‐regulated by HCV infection, which, in turn, stimulates HCV propagation and steatosis by disrupting insulin signaling; targeting CD2AP may offer an opportunity for alleviating HCV infection and its associated liver pathology. (Hepatology 2018;XX:XXX‐XXX.)

Hepatitis C virus nonstructural protein 5A perturbs lipid metabolism by modulating AMPK/SREBP-1c signaling

“…Its genome encodes a single polyprotein, which is processed by a combination of host and viral proteases to yield 10 individual proteins, including core, envelope 1 and 2 (E1 and E2), p7, and nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B). Nonstructural protein 5A (NS5A) has generated considerable interest in HCV research because of its ability to modulate the virus replication cycle, cell metabolism and host cell interferon response [5–10]. Although recent studies imply that the NS5A protein may play an important role in the pathological changes of HCV-associated hepatic steatosis by interacting with a variety of cellular proteins, the underlying molecular mechanisms remain largely elusive [11–14].…”

Insulin potentiates JAK/STAT signaling to broadly inhibit flavivirus replication in insect vectors

“…stephensi, overexpression of activated Akt in the midgut 317 blocked P. falciparum infection (Corby--Harris et al, 2010). In human cells, Akt signaling has 318 been connected to the immune response to the flavivirus hepatitis C virus (HCV)(Aytug et 319 al., 2003), and virus--induced disruption of insulin signaling was observed to increase HCV 320 replication(Zhang et al, 2018). A variety of studies suggest that insulin signaling--321 dependent activation of ERK contributes to this antiviral effect.…”

Analysis of eEF1Bγ interactome in the nuclear fraction of A549 human lung adenocarcinoma cells

“…In particular, it controls Aβ generation in dendritic early endosomes [37]. Also, CD2AP exemplifies pro-viral activity, for instance it binds unstructured subunits of Chikungunya virus replicase [38] and stimulates chronic hepatitis C virus propagation and steatosis by disrupting insulin signaling [39]. TIA1 (T cell intracellular antigen-1) is prion-related RNA-binding protein [40].…”