Vibrio parahaemolyticus effector proteins suppress inflammasome activation by interfering with host autophagy signaling.
Vibrio parahaemolyticus effector proteins suppress inflammasome activation by interfering with host autophagy signaling.
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DOI：
10.1371/journal.ppat.1003142
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发表时间：
2013-01
期刊：
影响因子：
6.7
通讯作者：
Suzuki T
中科院分区：
文献类型：
--
作者：
Higa N;Toma C;Koizumi Y;Nakasone N;Nohara T;Masumoto J;Kodama T;Iida T;Suzuki T
细菌病原体利用成孔毒素或复杂的分泌系统在宿主中建立感染。这些毒素或分泌系统被核苷酸结合寡聚化结构域富亮氨酸重复序列蛋白（NLR）识别，触发炎性小体的组装，这是半胱天冬酶-1活化和炎性细胞因子（如IL-1β或IL-18）成熟所必需的多蛋白复合物。在这里，我们证明了NLRP 3和NLRC 4炎性小体都被热稳定直接溶血素（TDH）和III型分泌系统1（T3 SS 1）激活，以响应副溶血性弧菌感染。此外，我们确定T3 SS 1分泌的效应蛋白，VopQ和VopS，诱导自噬和Cdc 42的失活，分别防止主要NLRC 4炎性小体激活。VopQ和VopS干扰感染的巨噬细胞中斑点的组装。这些数据表明，细菌效应子干扰炎性小体激活，并有助于细菌逃避宿主炎症反应。 副溶血性弧菌是引起人类食物中毒的革兰氏阴性致病菌。到目前为止，一些细菌的因素，发挥作用的副溶血性弧菌毒力的特点，但很少有人知道的宿主因素，有助于疾病的过程和对这些病原体的易感性。除了TNF-α之外，IL-1β被认为参与病原体感染期间的炎症反应和疾病发展，但IL-1β产生的机制仍然不清楚。在这项工作中，我们发现NLRP 3和NLRC 4炎性体都被热稳定直接溶血素（TDH）和III型分泌系统1（T3 SS 1）激活，以响应副溶血性弧菌感染。活化的炎性小体然后触发半胱天冬酶-1的活化，半胱天冬酶-1是IL-1β加工和释放所必需的半胱氨酸蛋白酶。此外，我们鉴定了T3 SS 1分泌的效应蛋白VopQ和VopS，其主要阻止NLRC 4炎性小体活化。VopQ和VopS分别诱导自噬和Rho GTP酶（包括Cdc 42）的失活，并且这些细胞事件干扰斑点的组装，斑点是炎性小体活化的平台。总的来说，基于T3 SS 1效应子的炎性小体激活抑制可能为细菌逃避炎性小体介导的宿主免疫应答的策略提供重要的见解。
Bacterial pathogens utilize pore-forming toxins or sophisticated secretion systems to establish infection in hosts. Recognition of these toxins or secretion system by nucleotide-binding oligomerization domain leucine-rich repeat proteins (NLRs) triggers the assembly of inflammasomes, the multiprotein complexes necessary for caspase-1 activation and the maturation of inflammatory cytokines such as IL-1β or IL-18. Here we demonstrate that both the NLRP3 and NLRC4 inflammasomes are activated by thermostable direct hemolysins (TDHs) and type III secretion system 1 (T3SS1) in response to V. parahaemolyticus infection. Furthermore, we identify T3SS1 secreted effector proteins, VopQ and VopS, which induce autophagy and the inactivation of Cdc42, respectively, to prevent mainly NLRC4 inflammasome activation. VopQ and VopS interfere with the assembly of specks in infected macrophages. These data suggest that bacterial effectors interfere with inflammasome activation and contribute to bacterial evasion from the host inflammatory responses. V. parahaemolyticus is Gram-negative pathogen that causes a food poisoning in human. To date, a number of bacterial factors that play a role in V. parahaemolyticus virulence have been characterized, yet little is known about the host factors contributing to the disease process and susceptibility to these pathogens. IL-1β, in addition to TNF-α, is thought to be involved in inflammatory responses and disease development during infection with the pathogen, but the mechanisms of IL-1β production remain poorly defined. In this work we found that both the NLRP3 and NLRC4 inflammasomes are activated by thermostable direct hemolysins (TDHs) and type III secretion system 1 (T3SS1) in response to V. parahaemolyticus infection. The activated inflammasomes then triggers the activation of caspase-1, a cysteine protease that is essential for IL-1β processing and release. Furthermore, we identified T3SS1 secreted effector proteins, VopQ and VopS, which prevent mainly NLRC4 inflammasome activation. VopQ and VopS induce autophagy and the inactivation of Rho GTPases, including Cdc42, respectively, and these cellular events interfere with the assembly of specks, the platform of inflammasome activation. Collectively, T3SS1 effector-based suppression of inflammasome activation may provide important insights into bacterial strategies for evading inflammasome-mediated host immune responses.
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影响因子：
3.6
作者：
Burdette DL;Seemann J;Orth K
通讯作者：
Orth K
影响因子：
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作者：
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64.8
作者：
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