Tripathi Anjali, Iyer Kruthika, Mitra Debashis
National Centre for Cell Science, Pune, India.
FEBS Lett. 2023 Dec;597(23):2908-2930. doi: 10.1002/1873-3468.14772. Epub 2023 Nov 20.
Several human diseases including viral infections activate the unfolded protein response (UPR) due to abnormal accumulation of unfolded/misfolded proteins. However, UPR modulation and its functional relevance in HIV-1 infection lack comprehensive elucidation. This study reveals that HIV-1 activates IRE1, PERK, and ATF6 signaling pathways of UPR. The knockdown of PERK and ATF6 reduces HIV-1 long terminal repeat (LTR)-driven gene expression, whereas the endoplasmic reticulum (ER) chaperone HSPA5 prevents proteasomal degradation of HIV-1 p24 through its chaperone activity. Interestingly, overstimulation of UPR by a chemical inducer leads to anti-HIV activity through an enhanced type-1 interferon response. Also, treatment with a chemical ER stress inhibitor reduces HIV-1 replication. These findings suggest that an optimal UPR activation is crucial for effective viral replication, as either overstimulating UPR or inhibiting ER stress leads to viral suppression.
包括病毒感染在内的多种人类疾病会因未折叠/错误折叠蛋白质的异常积累而激活未折叠蛋白反应（UPR）。然而，UPR调节及其在HIV-1感染中的功能相关性尚缺乏全面的阐释。本研究表明，HIV-1会激活UPR的IRE1、PERK和ATF6信号通路。PERK和ATF6的敲低会降低HIV-1长末端重复序列（LTR）驱动的基因表达，而内质网（ER）伴侣蛋白HSPA5通过其伴侣活性防止HIV-1 p24的蛋白酶体降解。有趣的是，化学诱导剂对UPR的过度刺激会通过增强1型干扰素反应而导致抗HIV活性。此外，用化学内质网应激抑制剂处理可减少HIV-1复制。这些发现表明，最佳的UPR激活对于有效的病毒复制至关重要，因为过度刺激UPR或抑制内质网应激都会导致病毒抑制。
