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Immunity. 2016 Jun 21;44(6):1392-405. doi: 10.1016/j.immuni.2016.05.007. Epub 2016 Jun 7.

Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk.

Author information

1
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: klassen@broadinstitute.org.
2
Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia.
3
Department of Cell Biology, University of Groningen, University Medical Center Groningen, 3713 AV Groningen, the Netherlands; Department of Cell Biology, University Medical Center Utrecht, 3564 CX Utrecht, the Netherlands.
4
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
5
Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Mater Research Institute and School of Medicine, University of Queensland, Brisbane, QLD 4101, Australia.
6
Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
7
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
8
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
9
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
10
Pathology Department, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA.
11
Garvan Institute of Medical Research and St. Vincent's Clinical School, University of New South Wales, Sydney, NSW 2010, Australia.
12
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA.
13
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: xavier@molbio.mgh.harvard.edu.

Abstract

Although numerous polymorphisms have been associated with inflammatory bowel disease (IBD), identifying the function of these genetic factors has proved challenging. Here we identified a role for nine genes in IBD susceptibility loci in antibacterial autophagy and characterized a role for one of these genes, GPR65, in maintaining lysosome function. Mice lacking Gpr65, a proton-sensing G protein-coupled receptor, showed increased susceptibly to bacteria-induced colitis. Epithelial cells and macrophages lacking GPR65 exhibited impaired clearance of intracellular bacteria and accumulation of aberrant lysosomes. Similarly, IBD patient cells and epithelial cells expressing an IBD-associated missense variant, GPR65 I231L, displayed aberrant lysosomal pH resulting in lysosomal dysfunction, impaired bacterial restriction, and altered lipid droplet formation. The GPR65 I231L polymorphism was sufficient to confer decreased GPR65 signaling. Collectively, these data establish a role for GPR65 in IBD susceptibility and identify lysosomal dysfunction as a potentially causative element in IBD pathogenesis with effects on cellular homeostasis and defense.

PMID:
27287411
PMCID:
PMC4936415
DOI:
10.1016/j.immuni.2016.05.007
[Indexed for MEDLINE]
Free PMC Article

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