Rezagholizadeh Neda, Datta Gaurav, Hasler Wendie A, Nguon Erica C, Smokey Elise V, Chen Xuesong
Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, USA.
Aging Cell. 2025 Apr 30:e70086. doi: 10.1111/acel.70086.
Cellular senescence contributes to accelerated aging, neuroinflammation, and the development of HIV-associated neurocognitive disorders (HAND) in the era of combined antiretroviral therapy (cART). One HIV viral factor that could lead to cellular senescence is the persistence of HIV-1 Tat in the brain. As a secreted viral protein, Tat is known to enter endolysosomes of cells through receptor-mediated endocytosis, and we have shown that Tat induces endolysosome damage and dysfunction. Significantly, endolysosome dysfunction has been strongly linked to cellular senescence. However, it is not known whether endolysosome dysfunction represents a driver or consequence of cellular senescence. Because Tat-induced endolysosome damage represents an early step in exogenous Tat-induced cellular senescence, we tested the hypothesis that Tat induces cellular senescence via an endolysosome-dependent mechanism in human astrocytes. We demonstrated that Tat interacts with an endolysosome-resident Toll-like receptor 7 (TLR7) via its arginine-rich basic domain, and such an interaction results in endolysosome damage and the development of a senescence-like phenotype including cell cycle arrest, enhanced SA-β-gal activity, and increased release of senescence-associated secretory phenotype (SASP) factors (IL-6, IL-8, and CCL2). Thus, our finding provided mechanistic insights whereby Tat induces endolysosome damage and cellular senescence in human astrocytes. We provide compelling evidence that endolysosome damage drives the development of cellular senescence. Our findings also highlight the novel role of TLR7 in the development of cellular senescence and suggest that TLR7 represents a novel therapeutic target against senescence and the development of HAND.
在联合抗逆转录病毒疗法（cART）时代，细胞衰老会加速衰老、引发神经炎症并导致HIV相关神经认知障碍（HAND）的发展。一种可能导致细胞衰老的HIV病毒因子是HIV-1反式激活因子（Tat）在大脑中的持续存在。作为一种分泌型病毒蛋白，Tat已知可通过受体介导的内吞作用进入细胞的内溶酶体，并且我们已经表明Tat会诱导内溶酶体损伤和功能障碍。重要的是，内溶酶体功能障碍与细胞衰老密切相关。然而，尚不清楚内溶酶体功能障碍是细胞衰老的驱动因素还是结果。由于Tat诱导的内溶酶体损伤是外源性Tat诱导细胞衰老的早期步骤，我们测试了Tat通过内溶酶体依赖性机制在人星形胶质细胞中诱导细胞衰老的假说。我们证明Tat通过其富含精氨酸的碱性结构域与内溶酶体驻留的Toll样受体7（TLR7）相互作用，这种相互作用导致内溶酶体损伤并产生类似衰老的表型，包括细胞周期停滞、增强的β-半乳糖苷酶（SA-β-gal）活性以及衰老相关分泌表型（SASP）因子（IL-6、IL-8和CCL2）释放增加。因此，我们的发现提供了Tat在人星形胶质细胞中诱导内溶酶体损伤和细胞衰老的机制性见解。我们提供了令人信服的证据表明内溶酶体损伤驱动细胞衰老的发展。我们的发现还突出了TLR7在细胞衰老发展中的新作用，并表明TLR7代表了对抗衰老和HAND发展的新治疗靶点。
