Genetic coding variant in GPR65 alters lysosomal pH and links lysosomal dysfunction with colitis risk

Lassen, Kara G., McKenzie, Craig I., Mari, Muriel, Murano, Tatsuro, Begun, Jakob, Baxt, Leigh A., Goel, Gautam, Villablanca, Eduardo J., Kuo, Szu-Yu, Huang, Hailiang, Macia, Laurence, Bhan, Atul K., Batten, Marcel, Daly, Mark J., Reggiori, Fulvio, Mackay, Charles R. and Xavier, Ramnik J. (2016) Genetic coding variant in GPR65 alters lysosomal pH and links lysosomal dysfunction with colitis risk. Immunity, 44 6: 1392-1405. doi:10.1016/j.immuni.2016.05.007

Author Lassen, Kara G.
McKenzie, Craig I.
Mari, Muriel
Murano, Tatsuro
Begun, Jakob
Baxt, Leigh A.
Goel, Gautam
Villablanca, Eduardo J.
Kuo, Szu-Yu
Huang, Hailiang
Macia, Laurence
Bhan, Atul K.
Batten, Marcel
Daly, Mark J.
Reggiori, Fulvio
Mackay, Charles R.
Xavier, Ramnik J.
Title Genetic coding variant in GPR65 alters lysosomal pH and links lysosomal dysfunction with colitis risk
Journal name Immunity   Check publisher's open access policy
ISSN 1097-4180
Publication date 2016-06-21
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.immuni.2016.05.007
Open Access Status Not Open Access
Volume 44
Issue 6
Start page 1392
End page 1405
Total pages 14
Place of publication Cambridge, MA, United States
Publisher Cell Press
Collection year 2017
Language eng
Formatted 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. Gene mapping efforts have identified numerous disease-associated genes, but understanding how these genes influence disease has proved challenging. Xavier and colleagues identify a role for GPR65 in lysosomal homeostasis and demonstrate that the IBD-associated risk variant GPR65 I231L confers lysosomal dysfunction with effects on autophagy, pathogen clearance, and intestinal homeostasis.
Keyword Inflammatory bowel disease
Lysosomal pH
Lysosomal dysfunction
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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