Zika virus NS2A protein induces the degradation of KPNA2 (karyopherin subunit alpha 2) via chaperone-mediated autophagy

Abstract

KPNA2/importin-alpha1 (karyopherin subunit alpha 2) is the primary nucleocytoplasmic transporter for some transcription factors to activate cellular proliferation and differentiation. Aberrant increase of KPNA2 level is identified as a prognostic marker in a variety of cancers. Yet, the turnover mechanism of KPNA2 remains unknown. Here, we demonstrate that KPNA2 is degraded via the chaperone-mediated autophagy (CMA) and that Zika virus (ZIKV) enhances the KPNA2 degradation. KPNA2 contains a CMA motif, which possesses an indispensable residue Gln109 for the CMA-mediated degradation. RNAimediated knockdown of LAMP2A, a vital component of the CMA pathway, led to a higher level of KPNA2. Moreover, ZIKV reduced KPNA2 via the viral NS2A protein, which contains an essential residue Thr100 for inducing the CMA-mediated KPNA2 degradation. Notably, mutant ZIKV with T100A alteration in NS2A replicates much weaker than the wild-type virus. Also, knockdown of KPNA2 led to a higher ZIKV viral yield, which indicates that KPNA2 mediates certain antiviral effects. These data provide insights into the KPNA2 turnover and the ZIKV-cell interactions.

Zika virus NS2A inhibits interferon signaling by degradation of STAT1 and STAT2

“…MG132 is often used to assess the involvement of the proteasome system in the virus induced-protein degradation [58]. Given that it also inhibits some lysosomal proteases [57], our results do not completely exclude the possibility of the involvement of the lysosomal proteolytic pathway in the degradation of both transcription factors. However, while the ubiquitination of STAT1 and STAT2 signaling proteins and their subsequent degradation in the proteasome system is the common and more frequent strategy adopted by several viruses, including Flavivirus, to shut down the innate immune response [26,[58][59][60][61][62], the virus-induced autophagic degradation of STAT1 and STAT2 as a mechanism for interferon signaling inhibition has been reported only by few papers [63,64].…”

“…Furthermore, it was recently reported that ZIKV-induced KPNA2 reduction is due to the lysosomal proteolysis as treatment with both MG132 and NH4Cl restores the KPNA2 level in ZIKV-infected cells and that such effect it is due to NS2A [ 57 ]. In our study, we demonstrated the effect of MG132 in restoring the levels of STAT1 and STAT2.…”

How SARS-CoV-2 and Other Viruses Build an Invasion Route to Hijack the Host Nucleocytoplasmic Trafficking System

“…Unlike the NS5 protein in Japanese encephalitis virus (JEV), which competes with the host IRF3 and NF-κB for α-importins (α1, α3, and α4) [124], ZIKV NS5 inhibits the activation of TANK-binding kinase 1 to prevent IRF3 activation [125], a strategy used to inhibit the IFN production by infected cells. Furthermore, ZIKV NS2A promotes the chaperone-mediated autophagy (CMA) of importin-α1 [126], possibly in an effort to suppress the host antiviral response.…”

The Role of Chaperone-Mediated Autophagy in Hepatitis C Virus-Induced Pathogenesis

“…Recently, it was reported that the NS2A protein of Zika virus promoted degradation of karyopherin subunit alpha 2 (KPNA2) via CMA, resulting in increased Zika virus production. The KNPA2 protein level was restored in the LAMP-2A knockdown cells infected with the Zika virus, indicating the important role of the CMA pathway in this viral replication ( He et al., 2020 ).…”