The E3 ubiquitin ligase RNF186 and RNF186 risk variants regulate innate receptor-induced outcomes.

Abstract

Balancing microbial-induced cytokines and microbial clearance is critical at mucosal sites such as the intestine. How the inflammatory bowel disease (IBD)-associated gene RNF186 regulates this balance is unclear. We found that macrophages from IBD-risk rs6426833 carriers in the RNF186 region showed reduced cytokines to stimulation through multiple pattern recognition receptors (PRRs). Upon stimulation of PRRs, the E3-ubiquitin ligase RNF186 promoted ubiquitination of signaling complex molecules shared across PRRs and those unique to select PRRs. Furthermore, RNF186 was required for PRR-initiated signaling complex assembly and downstream signaling. RNF186, along with its intact E3-ubiquitin ligase activity, was required for optimal PRR-induced antimicrobial reactive oxygen species, reactive nitrogen species, and autophagy pathways and intracellular bacterial clearance in human macrophages and for bacterial clearance in intestinal myeloid cells. Cells transfected with the rare RNF186-A64T IBD-risk variant and macrophages from common rs6426833 RNF186 IBD-risk carriers demonstrated a reduction in these RNF186-dependent outcomes. These studies identify mechanisms through which RNF186 regulates innate immunity and show that RNF186 IBD-risk variants demonstrate a loss of function in PRR-initiated outcomes.

• Authors: Kishu Ranjan, Matija Hedl, Clara Abraham
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 32 (08 10 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 34353900 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cytokines
• NF-kappa B
• NOD2 protein, human
• Nod2 Signaling Adaptor Protein
• Receptors, Pattern Recognition
• TLR2 protein, human
• TLR4 protein, human
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• RNF186 protein, human
• Ubiquitin-Protein Ligases
• RIPK2 protein, human
• Receptor-Interacting Protein Serine-Threonine Kinase 2

Topics

• Cytokines (metabolism)
• Humans
• Immunity, Innate
• Inflammatory Bowel Diseases (genetics, metabolism, microbiology, pathology)
• Intestines (cytology)
• Macrophages (metabolism, microbiology, pathology)
• Myeloid Cells (metabolism, pathology)
• NF-kappa B (metabolism)
• Nod2 Signaling Adaptor Protein (metabolism)
• Polymorphism, Single Nucleotide
• Receptor-Interacting Protein Serine-Threonine Kinase 2 (metabolism)
• Receptors, Pattern Recognition (metabolism)
• Toll-Like Receptor 2 (metabolism)
• Toll-Like Receptor 4 (metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Ubiquitination