A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity

Date

2005

Authors

Garcia De Vinuesa, Maria Carola
Cook, Matthew
Angelucci, C
Athanasopoulos, Vicki
Rui, Lixin
Hill, K
Yu, Di
Domaschenz, Heather
Whittle, Belinda
Lambe, Teresa

Journal Title

Journal ISSN

Volume Title

Publisher

Macmillan Publishers Ltd

Abstract

Despite the sequencing of the human and mouse genomes, few genetic mechanisms for protecting against autoimmune disease are currently known. Here we systematically screen the mouse genome for autoimmune regulators to isolate a mouse strain, sanroque, with severe autoimmune disease resulting from a single recessive defect in a previously unknown mechanism for repressing antibody responses to self. The sonroque mutation acts within mature T cells to cause formation of excessive numbers of follicular helper T cells and germinal centres. The mutation disrupts a repressor of ICOS, an essential co-stimulatory receptor for follicular T cells, and results in excessive production of the cytokine interleukin-21. sanroque mice fail to repress diabetes-causing T cells, and develop high titres of autoantibodies and a pattern of pathology consistent with lupus. The causative mutation is in a gene of previously unknown function, roquin (Rc3h1), which encodes a highly conserved member of the RING-type ubiquitin ligase protein family. The Roquin protein is distinguished by the presence of a CCCH zinc-finger found in RNA-binding proteins, and localization to cytosolic RNA granules implicated in regulating messenger RNA translation and stability.

Description

Keywords

Keywords: Antibodies; Binding energy; Diseases; Enzymes; Genes; Immunization; Living systems studies; Pathology; RNA; Autoimmune dieses; Autoimmune regulators; Autoimmunity; Follicular helper T cells; Ubiquitin ligase; Cells; autoantibody; interleukin 21; messenger

Citation

Source

Nature

Type

Journal article

Book Title

Entity type

Access Statement

License Rights

DOI

10.1038/nature03555

Restricted until

2037-12-31