Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong, China.
Shandong Provincial Key Laboratory of Zoonoses, Shandong Agricultural University, Taian, Shandong, China.
Commun Biol. 2024 Nov 5;7(1):1438. doi: 10.1038/s42003-024-07052-1.
Autophagy is a highly conserved degradative process that has been linked to various functions, including defending host cells against pathogens. Although the involvement of autophagy in porcine circovirus 2 (PCV2) infection has become apparent, it remains unclear whether selective autophagy plays a critical role in PCV2 restriction. Here we show that retinol-binding protein 4 (RBP4), an adipokine for retinol carrier, initiates the autophagic degradation of PCV2 ORF1 protein. PCV2 infection increases RBP4 protein levels through MAPK-eIF4E axis in living cells. Ectopic expression of RBP4 or recombinant RBP4 treatment promotes the degradation of ORF1 protein. Mechanistically, RBP4 activates TRAF6 to induce K63-linked ubiquitination of ORF1, leading to SQSTM1/p62-mediated selective autophagy for degradation. Consequently, RBP4 deficiency increases viral loads and exacerbates the pathogenicity of PCV2 in vivo. Collectively, these results identify RBP4 as a key host restriction factor of PCV2 and reveal a previously undescribed antiviral mechanism against PCV2 in infected cells.
自噬是一种高度保守的降解过程，与多种功能有关，包括保护宿主细胞免受病原体的侵害。虽然自噬在猪圆环病毒 2（PCV2）感染中的作用已经很明显，但自噬是否在 PCV2 的限制中起关键作用仍不清楚。在这里，我们表明视黄醇结合蛋白 4（RBP4），一种视黄醇载体的脂肪细胞因子，启动了 PCV2 ORF1 蛋白的自噬降解。PCV2 感染通过活细胞中的 MAPK-eIF4E 轴增加 RBP4 蛋白水平。异位表达 RBP4 或重组 RBP4 处理促进 ORF1 蛋白的降解。在机制上，RBP4 激活 TRAF6 诱导 ORF1 的 K63 连接泛素化，导致 SQSTM1/p62 介导的选择性自噬降解。因此，RBP4 缺乏会增加病毒载量，并在体内加剧 PCV2 的致病性。总之，这些结果表明 RBP4 是 PCV2 的关键宿主限制因子，并揭示了感染细胞中针对 PCV2 的一种以前未描述的抗病毒机制。
