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Updated: Mar 19, 2026
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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
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Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk
Kara G Lassen1, Craig I McKenzie2, Muriel Mari3
1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Immunity
|June 12, 2016
Summary
Genetic factors influence inflammatory bowel disease (IBD) risk. This study reveals G protein-coupled receptor 65 (GPR65) dysfunction impairs lysosome function, increasing susceptibility to IBD.
Area of Science:
- Immunology
- Genetics
- Cell Biology
Background:
- Numerous genetic polymorphisms are linked to inflammatory bowel disease (IBD) susceptibility.
- The functional roles of these genetic factors in IBD pathogenesis remain largely uncharacterized.
Purpose of the Study:
- To investigate the function of nine genes within IBD susceptibility loci in antibacterial autophagy.
- To characterize the role of G protein-coupled receptor 65 (GPR65) in lysosome function and IBD.
Main Methods:
- Utilized a mouse model lacking Gpr65 to assess susceptibility to bacteria-induced colitis.
- Examined epithelial cells and macrophages from Gpr65-deficient mice and IBD patients.
- Analyzed lysosomal pH, bacterial clearance, and lipid droplet formation in cellular models.
Main Results:
- Gpr65 deficiency in mice led to increased susceptibility to colitis.
- GPR65-deficient cells showed impaired intracellular bacterial clearance and aberrant lysosomes.
- An IBD-associated GPR65 variant (I231L) caused lysosomal dysfunction and impaired bacterial restriction.
Conclusions:
- GPR65 plays a crucial role in IBD susceptibility.
- Lysosomal dysfunction, driven by GPR65 alterations, is implicated in IBD pathogenesis.
- GPR65 impacts cellular homeostasis and defense mechanisms relevant to IBD.
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