RNF115 Inhibits the Post‐ER Trafficking of TLRs and TLRs‐Mediated Immune Responses by Catalyzing K11‐Linked Ubiquitination of RAB1A and RAB13. Issue 16 (28th March 2022)

• Record Type: Journal Article
• Authors: Zhang, Zhi‐Dong; Li, Hong‐Xu; Gan, Hu; Tang, Zhen; Guo, Yu‐Yao; Yao, Shu‐Qi; Liuyu, Tianzi; Zhong, Bo; Lin, Dandan
• Is Part Of: Advanced science. Volume 9:Issue 16(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-03-28
• Subjects: intracellular trafficking -- RAB proteins -- RNF115 -- signaling transduction -- Toll‐like receptors -- ubiquitination; Science -- Periodicals; 505
• DOI: 10.1002/advs.202105391
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: The subcellular localization and intracellular trafficking of Toll‐like receptors (TLRs) critically regulate TLRs‐mediated antimicrobial immunity and autoimmunity. Here, it is demonstrated that the E3 ubiquitin ligase RNF115 inhibits the post‐endoplasmic reticulum (ER) trafficking of TLRs and TLRs‐mediated immune responses by catalyzing ubiquitination of the small GTPases RAB1A and RAB13. It is shown that the 14‐3‐3 chaperones bind to AKT1‐phosphorylated RNF115 and facilitate RNF115 localizing on the ER and the Golgi apparatus. RNF115 interacts with RAB1A and RAB13 and catalyzes K11‐linked ubiquitination on the Lys49 and Lys61 residues of RAB1A and on the Lys46 and Lys58 residues of RAB13, respectively. Such a modification impairs the recruitment of guanosine diphosphate (GDP) dissociation inhibitor 1 (GDI1) to RAB1A and RAB13, a prerequisite for the reactivation of RAB proteins. Consistently, knockdown of RAB1A and RAB13 in Rnf115 +/+ and Rnf115 −/− cells markedly inhibits the post‐ER and the post‐Golgi trafficking of TLRs, respectively. In addition, reconstitution of RAB1A K49/61R or RAB13 K46/58R into Rnf115 +/+ cells but not Rnf115 −/− cells promotes the trafficking of TLRs from the ER to the Golgi apparatus and from the Golgi apparatus to the cell surface, respectively. These findings uncover a common and step‐wise regulatory mechanism for the post‐ER trafficking of TLRs. Abstract : Toll‐like receptors (TLRs) undergo ordered intracellular trafficking to subcellular compartments and plasma membrane where they recognize pathogen‐associated molecular patterns (PAMPs) for activation and signaling. Here, it is shown that RNF115 inhibits the endoplasmic reticulum (ER)‐Golgi and Golgi‐plasma membrane trafficking of TLRs by catalyzing ubiquitination of RAB1A and RAB13 respectively. These findings uncover a common and step‐wise regulatory mechanism for the post‐ER trafficking of TLRs.