PB1 Domain Interaction of p62/Sequestosome 1 and MEKK3 Regulates NF-κB Activation
PB1 Domain Interaction of p62/Sequestosome 1 and MEKK3 Regulates NF-κB Activation
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DOI：
10.1074/jbc.m109.065102
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发表时间：
2010-01-15
影响因子：
4.8
通讯作者：
Johnson, Gary L.
中科院分区：
文献类型：
--
作者：
Nakamura, Kazuhiro;Kimple, Adam J.;Johnson, Gary L.
p62/Sequestosome 1是一种支架蛋白，参与自噬的调节、蛋白质向蛋白酶体的运输和NF-κ B的活化。p62除了编码ZZ结构域、TRAF 6结合结构域、LC 3相互作用区和泛素相关结构域之外，还编码N-末端PB 1结构域，每个结构域对于p62的生理功能都是关键的。PB 1结构域具有β-抓握拓扑结构，其中一个PB 1结构域的前端结合第二个PB 1结构域的后端。p62 PB 1结构域与其他PB 1结构域同源二聚化以及异源二聚化。p62中PB 1结构域的前端结合非典型蛋白激酶C、MAPK激酶、MEK 5和NBR 1蛋白的PB 1结构域。除了其在同源二聚化中的作用之外，p62 PB 1结构域的后端酸性簇区域没有先前定义的结合伴侣。在此，我们证明，后端的p62 PB 1结构域的酸性簇区域结合的MAPK激酶激酶，MEKK 3的前端碱性区域。p62和MEKK 3共定位于斑点或聚集体中，所述斑点或聚集体是组织TRAF 6调节的NF-κ B信号传导和分选成多聚泛素化蛋白质的多聚泛素化蛋白质组装成多价螯合体和蛋白酶体的中心。p62-MEKK 3复合物结合TRAF 6，TRAF 6调节IKK复合物的泛素化和NF-κ B活化。p62是MEKK 3与TRAF 6结合所必需的，并且p62的短发夹RNA敲低抑制IL-1和NF-κ B的MEKK 3活化。p62 PB 1结构域的后端酸性簇用于组织胞质聚集体或斑点相关的TRAF 6-p62-MEKK 3复合物，以控制NF-κ B活化。
p62/Sequestosome 1 is a scaffold protein involved in the regulation of autophagy, trafficking of proteins to the proteasome, and activation of NF-kappa B. p62 encodes an N-terminal PB1 domain in addition to the ZZ domain, TRAF6-binding domain, LC3 interaction region, and ubiquitin-associated domain, each critical for the physiological function of p62. PB1 domains have a beta-grasp topology where the front end of one PB1 domain binds the back end of a second PB1 domain. The p62 PB1 domain homodimerizes as well as heterodimerizes with other PB1 domains. The front end of the PB1 domain in p62 binds the PB1 domain of atypical protein kinases C, the MAPK kinase, MEK5, and the NBR1 protein. Other than its role in homodimerization, the rear end acidic cluster region of the p62 PB1 domain had no previous defined binding partners. Herein, we demonstrate that the rear end acidic cluster region of the p62 PB1 domain binds the front end basic region of the MAPK kinase kinase, MEKK3. p62 and MEKK3 co-localize in speckles or aggregates that are centers for organizing TRAF6-regulated NF-kappa B signaling and the assembly of polyubiquinated proteins sorting to sequestosomes and proteasomes. The p62-MEKK3 complex binds TRAF6, which regulates the ubiquitination of the IKK complex and NF-kappa B activation. p62 is required for the association of MEKK3 with TRAF6 and short hairpin RNA knockdown of p62 inhibits IL-1 and MEKK3 activation of NF-kappa B. The rear end acidic cluster of the p62 PB1 domain is used to organize cytosolic aggregates or speckles-associated TRAF6-p62-MEKK3 complex for control of NF-kappa B activation.