Yoshida Hiroki, Jono Hirofumi, Kai Hirofumi, Li Jian-Dong
Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, California 90057, USA.
J Biol Chem. 2005 Dec 9;280(49):41111-21. doi: 10.1074/jbc.M509526200. Epub 2005 Oct 17.
Toll-like receptor 2 (TLR2) plays an important role in host defense against bacterial pathogens. Activation of TLR2 signaling not only induces the activation of innate immunity and instructs the development of the acquired immunity but also leads to the detrimental inflammatory responses in inflammatory and infectious diseases. To avoid detrimental inflammatory responses, TLR2 signaling must be tightly regulated. In contrast to the relative known positive regulation of TLR2 signaling, its negative regulation, however, is largely unknown. In addition the distal signaling components that link TLR2 to its downstream signaling pathways have yet to be further defined. In the present study we have provided direct evidence for the negative regulation of TLR2 signaling by the tumor suppressor cylindromatosis (CYLD). We showed that activation of TLR2 signaling by TLR2 ligands including peptidoglycan (PGN), MALP-2, and Pam3CSK4 induces activation of IKKs-IkappaBalpha and MKK3/6-p38 pathways not only by TRAF6 but also by TRAF7, a recently identified TRAF family member. The activation of both pathways leads to the transcription of TNF-alpha, IL-1beta, and IL-8 as well as CYLD. CYLD in turn leads to the inhibition of TRAF6 and TRAF7 likely via a deubiquitination-dependent mechanism. The present studies thus unveil a novel autoregulatory feedback mechanism that negatively controls TLR2-IKKs-IkappaBalpha/MKK3/6-p38-NF-kappaB-dependent induction of immune and inflammatory responses via negatively cross-talking with both TRAF6 and TRAF7. These findings provide novel insights into autoregulation and negative regulation of TLR signaling.
Toll样受体2（TLR2）在宿主抵御细菌病原体的防御中发挥着重要作用。TLR2信号通路的激活不仅诱导先天免疫的激活并指导获得性免疫的发展，还会在炎症和感染性疾病中引发有害的炎症反应。为避免有害的炎症反应，TLR2信号通路必须受到严格调控。与相对已知的TLR2信号通路的正向调控相反，其负向调控在很大程度上尚不清楚。此外，将TLR2与其下游信号通路相连的远端信号成分还有待进一步明确。在本研究中，我们提供了肿瘤抑制因子圆柱瘤蛋白（CYLD）对TLR2信号通路进行负向调控的直接证据。我们发现，包括肽聚糖（PGN）、MALP-2和Pam3CSK4在内的TLR2配体激活TLR2信号通路，不仅通过肿瘤坏死因子受体相关因子6（TRAF6），还通过最近鉴定出的TRAF家族成员TRAF7诱导IKK - IκBα和MKK3/6 - p38信号通路的激活。这两条信号通路的激活均导致肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-8（IL-8）以及CYLD的转录。CYLD继而可能通过去泛素化依赖机制导致TRAF6和TRAF7的抑制。因此，本研究揭示了一种新的自调节反馈机制，该机制通过与TRAF6和TRAF7的负向相互作用，负向控制TLR2 - IKKs - IκBα/MKK3/6 - p38 - 核因子κB（NF-κB）依赖的免疫和炎症反应诱导。这些发现为TLR信号通路的自调节和负向调控提供了新的见解。
