NLRP4 negatively regulates autophagic processes through an association with beclin1.

在这项研究中，我们证明了NLRP4通过其Nacht结构域与自噬的重要调节因子Beclin1相互作用。在这些NLR中，NLRP4与Beclinl进化保守结构域有很强的亲和力。通过RNA干扰使NLRP4在生理条件下和侵袭性细菌感染时自噬过程上调，从而增强对A组链球菌(GAS)的自噬杀菌过程。NLRP4被募集到含有GAS的亚质膜噬菌体上，并与Beclin1暂时解离，这表明NLRP4感知细菌感染并允许Beclin1介导的自噬反应的启动。除了作为自噬过程的负调节因子外，NLRP4还与C类空泡蛋白分选(C-VPS)复合体结合，从而负向调节自噬小体和内噬小体的成熟。总之，这些结果提供了新的证据，表明NLRP4，可能还有NLR家族的其他一些成员，通过与Beclinl和C-VPS复合体等调节分子的结合，在自噬小体的生物发生及其成熟中发挥关键作用。

In this study, we show that NLRP4 interact with Beclin1, an important regulator of autophagy, through their NACHT domain. Among such NLRs, NLRP4 had a strong affinity to the Beclinl evolutionally conserved domain. Conlpromising NLRP4 via RNA interference resulted in an upregulation of the autophagic process under physiological conditions and upon invasive bacterial infections, leading to enhancement of the autophagic bactericidal process against group A streptococcus (GAS). NLRP4 recruited to the sub-plasma membrane phagosomes containing GAS and transiently dissociated from Beclin1, suggesting that NLRP4 senses bacterial infection and permits the initiation of Beclin1-mediated autophagic responses. In addition to such a role as a negative regulator of the autophagic process, NLRP4 physically associates with the class C vacuolar protein sorting (C-VPS) complex, thereby negatively regulates the maturation of the autophagosome and endosome. Collectively, these results provide novel evidence that NLRP4, and possibly some other members of the NLR family, play a crucial role in biogenesis of the autophagosome and its maturation by the association with the regulatory molecules such as Beclinl and the C-VPS complex.