Cell Death and Aging Team, Gustave Roussy, 114 rue Edouard Vaillant, F-94805 Villejuif, France; Laboratory of Molecular Radiotherapy, INSERM U1030, Gustave Roussy, 114 rue Edouard Vaillant, F-94805 Villejuif, France; Gustave Roussy, 114 rue Edouard Vaillant, F-94805 Villejuif, France; Université Paris Sud - Paris 11, 114 rue Edouard Vaillant, F-94805 Villejuif, France.
Gustave Roussy, 114 rue Edouard Vaillant, F-94805 Villejuif, France; Université Paris Sud - Paris 11, 114 rue Edouard Vaillant, F-94805 Villejuif, France; INSERM U848, Gustave Roussy, 114 rue Edouard Vaillant, F-94805 Villejuif, France.
Cell Rep. 2019 Sep 24;28(13):3381-3394.e7. doi: 10.1016/j.celrep.2019.02.095.
Purinergic receptors and nucleotide-binding domain leucine-rich repeat containing (NLR) proteins have been shown to control viral infection. Here, we show that the NLR family member NLRP3 and the purinergic receptor P2Y2 constitutively interact and regulate susceptibility to HIV-1 infection. We found that NLRP3 acts as an inhibitory factor of viral entry that represses F-actin remodeling. The binding of the HIV-1 envelope to its host cell receptors (CD4, CXCR4, and/or CCR5) overcomes this restriction by stimulating P2Y2. Once activated, P2Y2 enhances its interaction with NLRP3 and stimulates the recruitment of the E3 ubiquitin ligase CBL to NLRP3, ultimately leading to NLRP3 degradation. NLRP3 degradation is permissive for PYK2 phosphorylation (PYK2Y402) and subsequent F-actin polymerization, which is required for the entry of HIV-1 into host cells. Taken together, our results uncover a mechanism by which HIV-1 overcomes NLRP3 restriction that appears essential for the accomplishment of the early steps of HIV-1 entry.
嘌呤能受体和核苷酸结合域富含亮氨酸重复（NLR）蛋白已被证明可以控制病毒感染。在这里，我们表明 NLR 家族成员 NLRP3 和嘌呤能受体 P2Y2 相互作用并调节对 HIV-1 感染的易感性。我们发现 NLRP3 作为病毒进入的抑制因子，抑制 F-actin 重塑。HIV-1 包膜与其宿主细胞受体（CD4、CXCR4 和/或 CCR5）的结合通过刺激 P2Y2 克服了这种限制。一旦被激活，P2Y2 增强与 NLRP3 的相互作用，并刺激 E3 泛素连接酶 CBL 向 NLRP3 的募集，最终导致 NLRP3 降解。NLRP3 降解允许 PYK2 磷酸化（PYK2Y402）和随后的 F-actin 聚合，这是 HIV-1 进入宿主细胞所必需的。总之，我们的研究结果揭示了 HIV-1 克服 NLRP3 限制的机制，这对于 HIV-1 进入的早期步骤的完成似乎是必不可少的。
