NLRP4 Negatively Regulates Autophagic Processes through an Association with Beclin1
NLRP4 Negatively Regulates Autophagic Processes through an Association with Beclin1
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DOI：
10.4049/jimmunol.1001654
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发表时间：
2011-02-01
影响因子：
4.4
通讯作者：
Takeshita, Fumihiko
中科院分区：
文献类型：
--
作者：
Jounai, Nao;Kobiyama, Kouji;Takeshita, Fumihiko
虽然超过20个假定的成员被分配到核苷酸结合和寡聚化结构域样受体（NLR）家族，但它们的生理和生物学作用，除了炎性体，尚未完全了解。在本文中，我们发现NLR成员，如NLRC4、NLRP3、NLRP4和NLRP10，通过其神经元凋亡抑制蛋白、MHC II类转录激活因子、来自猪尾孢虫的不相容位点蛋白和端粒酶相关蛋白域与Beclin1（一种重要的自噬调节因子）相互作用。在这些NLRs中，NLRP4与Beclin1进化保守结构域具有很强的亲和力。通过RNA干扰损害NLRP4，导致生理条件下和侵袭性细菌感染时自噬过程上调，导致A群链球菌自噬杀菌过程增强。NLRP4被招募到含有A群链球菌的亚质膜吞噬体中，并与Beclin1短暂分离，这表明NLRP4感知细菌感染并允许启动Beclin1介导的自噬反应。除了作为自噬过程的负调节因子外，NLRP4在物理上与C类空泡蛋白分选复合体相关，从而负向调节自噬体和内体的成熟。总的来说，这些结果提供了新的证据，证明NLRP4和NLR家族的其他成员可能通过与Beclin1和C类空泡蛋白分选复合物等调节分子的关联，在自噬体的生物发生及其成熟中起着至关重要的作用。免疫学杂志，2011,18(6):1646-1655。
Although more than 20 putative members have been assigned to the nucleotide-binding and oligomerization domain-like receptor (NLR) family, their physiological and biological roles, with the exception of the inflammasome, are not fully understood. In this article, we show that NLR members, such as NLRC4, NLRP3, NLRP4, and NLRP10 interact with Beclin1, an important regulator of autophagy, through their neuronal apoptosis inhibitory protein, MHC class II transcription activator, incompatibility locus protein from Podospora anserina, and telomerase-associated protein domain. Among such NLRs, NLRP4 had a strong affinity to the Beclin1 evolutionally conserved domain. Compromising NLRP4 via RNA interference resulted in upregulation of the autophagic process under physiological conditions and upon invasive bacterial infections, leading to enhancement of the autophagic bactericidal process of group A streptococcus. NLRP4 recruited to the subplasma membrane phagosomes containing group A streptococcus and transiently dissociated from Beclin1, suggesting that NLRP4 senses bacterial infection and permits the initiation of Beclin1-mediated autophagic responses. In addition to a role as a negative regulator of the autophagic process, NLRP4 physically associates with the class C vacuolar protein-sorting complex, thereby negatively regulating maturation of the autophagosome and endosome. Collectively, these results provide novel evidence that NLRP4, and possibly other members of the NLR family, plays a crucial role in biogenesis of the autophagosome and its maturation by the association with regulatory molecules, such as Beclin1 and the class C vacuolar protein-sorting complex. The Journal of Immunology, 2011, 186: 1646-1655.