The role of TRIM37 in immune signaling

• Main Authors: Wei-Yu Huang, 黃薇毓
• Other Authors: Ping-Hui Tseng
• Format: Others
• Language: zh-TW
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/28883650316292471106

碩士 === 國立陽明大學 === 生化暨分子生物研究所 === 102 === The MATH domain, which is also called the TRAF-C domain, is defined as a binding domain. The TRAF family proteins are most well-known MATH domain-containing proteins. In addition, TRAFs have RING domain with E3 ligase activity that are important for downstream signaling events. The TRAF family proteins were originally identified as adaptor proteins that interact with the receptors of the TNFR family and, then found to mediate signaling from several other receptors, including TLRs, NLRs, RLRs, IL-1R, Il-17R and IFNR. TRAFs-mediate signaling pathways typically lead to the activation of NF-κB, MAPKs and IRFs, and are thought to be important regulators to cell death, immune response and stress response. We are interested in TRIM37, which is a MATH and RING domain-containing protein, like TRAF proteins. But TRIM37 belongs to the TRIM family that contains RBCC domain (RING, B-Box and Coiled-coil domain) . Several studies about TRIM37 have been focused on a rare autosomal recessive disorder─Mulibrey nanism (MUL) , that is associated with a recessive defect in the gene TRIM37. Additionally, the previous study demonstrated that TRIM37 interacts with TRAF proteins, TNFR2, LTR and other TNFRs. But the biological function and molecular regulation of TRIM37 is still unclear. Based on the structure similarily of TRIM37 and TRAF proteins, we focused on studying the role of TRIM37 in TRAFs associated signaling. We found that TRIM37 is degraded by proteasome in reponse to TLR4 and TNFR1 signaling. By knocking down TRIM37 with shRNA, we found that a reduction in TLR4 and TNFR1 mediated in mRNA expression, such as Tnf, Il-6, Il-10. TRAF2 and 3 expression level were declined in TRIM37-knocked-down cells, but upregulated in TRIM37-overexpressed cells, indicating that the level of TRIM37 is correlated with TRAF2 and TRAF3. Otherwise, TRIM37 underwent auto-ubiquitination and was modified with both K48 and K63-linked ubiquitination. We showed that K437 is the site for K63-linked ubiquitination. Our results suggest that TRIM37 is critical for TLR4 and TNFR1 pathways, and is associated with TRAF2 and TRAF3 protein levels.