The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunity

Alicia Gonzalez-Martin; Brian D Adams; Maoyi Lai; Jovan Shepherd; Maria Salvador-Bernaldez; Jesus M Salvador; Jun Lu; David Nemazee; Changchun Xiao

doi:10.1038/ni.3385

The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunity

Nat Immunol. 2016 Apr;17(4):433-40. doi: 10.1038/ni.3385. Epub 2016 Feb 22.

Authors

Alicia Gonzalez-Martin¹, Brian D Adams², Maoyi Lai¹, Jovan Shepherd¹, Maria Salvador-Bernaldez³, Jesus M Salvador³, Jun Lu², David Nemazee¹, Changchun Xiao¹

Affiliations

¹ Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
² Department of Genetics, Yale Stem Cell Center, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University, New Haven, Connecticut, USA.
³ Department of Immunology and Oncology, National Biotechnology Center, Madrid, Spain.

PMID: 26901150
PMCID: PMC4803625
DOI: 10.1038/ni.3385

Abstract

Autoreactive B cells have critical roles in a large diversity of autoimmune diseases, but the molecular pathways that control these cells remain poorly understood. We performed an in vivo functional screen of a lymphocyte-expressed microRNA library and identified miR-148a as a potent regulator of B cell tolerance. Elevated miR-148a expression impaired B cell tolerance by promoting the survival of immature B cells after engagement of the B cell antigen receptor by suppressing the expression of the autoimmune suppressor Gadd45α, the tumor suppressor PTEN and the pro-apoptotic protein Bim. Furthermore, increased expression of miR-148a, which occurs frequently in patients with lupus and lupus-prone mice, facilitated the development of lethal autoimmune disease in a mouse model of lupus. Our studies demonstrate a function for miR-148a as a regulator of B cell tolerance and autoimmunity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics*
Apoptosis / immunology
Apoptosis Regulatory Proteins / metabolism
Autoimmunity / genetics*
Autoimmunity / immunology
B-Lymphocytes / immunology*
Bcl-2-Like Protein 11
Bone Marrow Transplantation
Cell Cycle Proteins / metabolism
Cell Proliferation / genetics
Disease Models, Animal
HEK293 Cells
Humans
Immune Tolerance / genetics*
Immune Tolerance / immunology
Immunoblotting
Lupus Erythematosus, Systemic / immunology
Membrane Proteins / metabolism
Mice
Mice, Inbred MRL lpr
MicroRNAs / genetics*
MicroRNAs / immunology
Nuclear Proteins / metabolism
PTEN Phosphohydrolase / metabolism
Proto-Oncogene Proteins / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Sequence Analysis, RNA

Substances

Apoptosis Regulatory Proteins
BCL2L11 protein, human
Bcl-2-Like Protein 11
Bcl2l11 protein, mouse
Cell Cycle Proteins
Gadd45a protein, mouse
Membrane Proteins
MicroRNAs
Mirn148 microRNA, mouse
Nuclear Proteins
Proto-Oncogene Proteins
PTEN Phosphohydrolase
Pten protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding