半胱氨酸天冬氨酸蛋白酶（caspase）介导的切割、IAP 结合和泛素化：连接三个对果蝇 NF-κB 信号至关重要的机制。
Caspase-mediated cleavage, IAP binding, and ubiquitination: linking three mechanisms crucial for Drosophila NF-kappaB signaling.
机构信息
Division of Infectious Disease, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
出版信息
Mol Cell. 2010 Jan 29;37(2):172-82. doi: 10.1016/j.molcel.2009.12.036.
Abstract
Innate immune responses are critical for the immediate protection against microbial infection. In Drosophila, infection leads to the rapid and robust production of antimicrobial peptides through two NF-kappaB signaling pathways-IMD and Toll. The IMD pathway is triggered by DAP-type peptidoglycan, common to most Gram-negative bacteria. Signaling downstream from the peptidoglycan receptors is thought to involve K63 ubiquitination and caspase-mediated cleavage, but the molecular mechanisms remain obscure. We now show that PGN stimulation causes caspase-mediated cleavage of the imd protein, exposing a highly conserved IAP-binding motif (IBM) at its neo-N terminus. A functional IBM is required for the association of cleaved IMD with the ubiquitin E3-ligase DIAP2. Through its association with DIAP2, IMD is rapidly conjugated with K63-linked polyubiquitin chains. These results mechanistically connect caspase-mediated cleavage and K63 ubiquitination in immune-induced NF-kappaB signaling.
摘要
先天免疫反应对于立即抵御微生物感染至关重要。在果蝇中，感染通过两种 NF-κB 信号通路——IMD 和 Toll 导致抗菌肽的快速和强烈产生。IMD 通路由 DAP 型肽聚糖触发，该肽聚糖存在于大多数革兰氏阴性菌中。肽聚糖受体下游的信号转导被认为涉及 K63 泛素化和半胱天冬酶介导的切割，但分子机制仍不清楚。我们现在表明，PGN 刺激导致 imd 蛋白的半胱天冬酶介导切割，在其新的 N 末端暴露高度保守的 IAP 结合基序 (IBM)。功能性 IBM 对于切割的 IMD 与泛素 E3 连接酶 DIAP2 的结合是必需的。通过与 DIAP2 的关联，IMD 与 K63 连接的多泛素链迅速缀合。这些结果从机制上连接了免疫诱导的 NF-κB 信号中半胱天冬酶介导的切割和 K63 泛素化。
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