RNF167‐mediated ubiquitination of Tollip inhibits TNF‐α‐triggered NF‐κB and MAPK activation

Abstract

Toll‐interacting protein (Tollip) is a multifunctional regulator in cellular activities. However, whether its functions are subjected to post‐translational modifications remains elusive. Here, we identified ubiquitination as a post‐translational modification on Tollip. We found that Tollip interacted with ring finger protein 167 (RNF167) through its C‐terminal coupling of ubiquitin to ER degradation (CUE) domain, and RNF167 functioned as the potential E3 ligase to attach K33‐linked poly‐ubiquitin chains to the Lys235 (K235) site of Tollip. Furthermore, we discovered Tollip could inhibit TNF‐α‐induced nuclear factor‐kappa B (NF‐κB) and mitogen‐activated protein kinase (MAPK) activation, and substitution of Lys235 on Tollip to arginine failed to suppress TNF‐α‐NF‐κB/MAPK (JNK) cascades, revealing the role of Tollip and its ubiquitination in NF‐κB/MAPK pathways. Thus, our study reveals the novel biological function of Tollip and RNF167‐dependent ubiquitination of Tollip in TNF‐α signaling.

Targeting TNF/IL-17/MAPK pathway in h<i>E2A-PBX1</i> leukemia: effects of OUL35, KJ-Pyr-9, and CID44216842

“…KJ-Pyr-9 did not improve the death of h E2A-PBX1 zebrafish, which may be due to other side effects caused by long-term treatment of KJ-Pyr-9. It has been reported that TNF 42-44 and IL-17 45-47 can activate the MAPK pathway. In order to investigate whether TNF/IL-17 can similarly activate the MAPK signaling in Tg(hsp70:E2APBX1-EGFP) , we treated 4 dpf hE2A-PBX1 embryos with TNF-α inhibitors pomalidomide and lenalidomide, as well as IL-17 inhibitor Y-320.…”

The First Discovery of Marine Polyoxygenated Cembranolides as Potential Agents for the Treatment of Ulcerative Colitis

“…We focused on the TNF signaling pathway, which is well-known to play a crucial role in macrophage activation and the inflammatory response. TNF is the most typical inducer of NF-κB and MAPK pathway activation and participates in macrophage M1 polarization. , We evaluated the effects of compounds 8 and 9 on the NF-κB and MAPK pathways in LPS-induced RAW246.7 cells. A NF-κB luciferase reporting system was used to identify the transcriptional inhibition effects of compounds 8 and 9 , and the results showed that compounds 8 and 9 could inhibit the transcriptional activity of NF-κB (Figure D).…”