Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk.
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.
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.
Kara G
KG
Lassen
Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia.
Craig I
CI
McKenzie
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.
Muriel
M
Mari
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Tatsuro
T
Murano
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.
Jakob
J
Begun
Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Leigh A
LA
Baxt
Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Gautam
G
Goel
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.
Eduardo J
EJ
Villablanca
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Szu-Yu
SY
Kuo
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.
Hailiang
H
Huang
Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia.
Laurence
L
Macia
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.
Atul K
AK
Bhan
Garvan Institute of Medical Research and St. Vincent's Clinical School, University of New South Wales, Sydney, NSW 2010, Australia.
Marcel
M
Batten
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.
Mark J
MJ
Daly
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.
Fulvio
F
Reggiori
Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia.
Charles R
CR
Mackay
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.
Ramnik J
RJ
Xavier
D000818:Animals; D003092:Colitis / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000276:immunology; D008247:Lysosomes / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010588:Phagosomes / Q000502:physiology; D011110:Polymorphism, Genetic; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012306:Risk; D012480:Salmonella Infections / Q000276:immunology*; D019779:Salmonella enterica / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology*
C513334:GPR65 protein, human; D043562:Receptors, G-Protein-Coupled