2. Academic Validation
  3. RNF115 Inhibits the Post-ER Trafficking of TLRs and TLRs-Mediated Immune Responses by Catalyzing K11-Linked Ubiquitination of RAB1A and RAB13

RNF115 Inhibits the Post-ER Trafficking of TLRs and TLRs-Mediated Immune Responses by Catalyzing K11-Linked Ubiquitination of RAB1A and RAB13

  • Adv Sci (Weinh). 2022 May;9(16):e2105391. doi: 10.1002/advs.202105391.
Zhi-Dong Zhang 1 2 3 4,  Hong-Xu Li 1 2 3,  Hu Gan 1 2 3 5,  Zhen Tang 1 2 3 5,  Yu-Yao Guo 1 2 3,  Shu-Qi Yao 1 2 3 5,  Tianzi Liuyu 1,  Bo Zhong 1 2 3 5 6,  Dandan Lin 4
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
  • 2 Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
  • 3 Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 430071, China.
  • 4 Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430061, China.
  • 5 Department of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
  • 6 Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, 430071, China.
PMID: 35343654 DOI: 10.1002/advs.202105391
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 RAB1AK49/61R or RAB13K46/58R 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.

Keywords

RAB proteins; RNF115; Toll-like receptors; intracellular trafficking; signaling transduction; ubiquitination.

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