TRIM40 promotes neddylation of IKK  and is downregulated in gastrointestinal cancers

Abstract

Gastrointestinal neoplasia seems to be a common consequence of chronic inflammation in the gastrointestinal epithelium. Nuclear factor-kappaB (NF-κB) is an important transcription factor for carcinogenesis in chronic inflammatory diseases and plays a key role in promoting inflammation-associated carcinoma in the gastrointestinal tract. Activation of NF-κB is regulated by several posttranslational modifications including phosphorylation, ubiquitination and neddylation. In this study, we showed that tripartite motif (TRIM) 40 is highly expressed in the gastrointestinal tract and that TRIM40 physically binds to Nedd8, which is conjugated to target proteins by neddylation. We also found that TRIM40 promotes the neddylation of inhibitor of nuclear factor kappaB kinase subunit gamma, which is a crucial regulator for NF-κB activation, and consequently causes inhibition of NF-κB activity, whereas a dominant-negative mutant of TRIM40 lacking the RING domain does not inhibit NF-κB activity. Knockdown of TRIM40 in the small intestinal epithelial cell line IEC-6 caused NF-κB activation followed by increased cell growth. In addition, we found that TRIM40 is highly expressed in normal gastrointestinal epithelia but that TRIM40 is downregulated in gastrointestinal carcinomas and chronic inflammatory lesions of the gastrointestinal tract. These findings suggest that TRIM40 inhibits NF-κB activity via neddylation of inhibitor of nuclear factor kappaB kinase subunit gamma and that TRIM40 prevents inflammation-associated carcinogenesis in the gastrointestinal tract.

TRIM45 negatively regulates NF-κB-mediated transcription and suppresses cell proliferation

“…Moreover, some members of the TRIM family of ubiquitin ligases have been shown to be involved in the regulation of these signaling pathways [23,28,31,32]. Thus, it is important to clarify the correlation between the functions of TRIM family ubiquitin ligases and the effects of these signaling pathways.…”

“…Moreover, we revealed that TRIM40, which is also one of the TRIM family ubiquitin ligases, enhanced neddylation of inhibitor of kappa B (I B) kinase (IKK) and inhibited the activity of NF-B-mediated transcription [28]. It has been reported that TRIM45 suppresses transcriptional activities of E twenty-six (ETS)-like transcription factor 1 (Elk-1) and activator protein 1 (AP-1), which are targets of the MAPK signaling pathway [23].…”

TRIM39 negatively regulates the NFκB-mediated signaling pathway through stabilization of Cactin

“…For example, we revealed that TRIM40, which is one of the TRIM family of ubiquitin ligases, enhances neddylation of IKKγ and inhibits the activity of NFκB-mediated transcription [25]. Moreover, we found that TRIM59 interacts with a signal adaptor protein, evolutionarily conserved signaling intermediate in Toll pathways (ECSIT), and negatively regulates NFκB and IRF3/7 signal pathways [24].…”

“…Based on our previous findings that some of the TRIM family proteins affect the stabilities of their binding proteins [13,14,[24][25][26], we speculated that TRIM39 affects the stability of Cactin. Although we assumed that TRIM39 promotes degradation of Cactin, protein stability analysis with cycloheximide revealed that overexpression of TRIM39 WT or that of ΔRING promoted the stabilization of Cactin protein (Fig.…”

A regulatory mutant on TRIM26 conferring the risk of nasopharyngeal carcinoma by inducing low immune response

“…TRIM26 is a member of the tripartite motif (TRIM) protein family composed of more than 70 members in human 29. In recent years, the TRIM protein family, such as TRIM3 , TRIM16 , TRIM28 , and TRIM40 , have been reported for their roles in cancers 30, 31, 32, 33. However, to date, its role in tumor remains unclear.…”