Summary

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. RNAi-mediated 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.

概括

KPNA2/importin-alpha1（karyopherin 亚基 alpha 2）是一些转录因子激活细胞增殖和分化的主要核质转运蛋白。KPNA2 水平的异常升高被确定为多种癌症的预后标志物。然而，KPNA2 的周转机制仍然未知。在这里，我们证明 KPNA2 通过伴侣介导的自噬 (CMA) 降解，并且寨卡病毒 (ZIKV) 增强了 KPNA2 降解。KPNA2 包含一个 CMA 基序，它具有 CMA 介导的降解不可或缺的残基 Gln109。RNAi 介导的 LAMP2A（CMA 通路的重要组成部分）敲低导致更高水平的 KPNA2。此外，ZIKV 通过病毒 NS2A 蛋白减少 KPNA2，NS2A 蛋白含有一个必需的残基 Thr100，可诱导 CMA 介导的 KPNA2 降解。尤其，在 NS2A 中具有 T100A 改变的突变 ZIKV 复制比野生型病毒弱得多。此外，KPNA2 的敲低导致更高的 ZIKV 病毒产量，这表明 KPNA2 介导了某些抗病毒作用。这些数据提供了对 KPNA2 营业额和 ZIKV 细胞相互作用的见解。