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

Kara G. Lassen, Craig I. McKenzie, Muriel Mari, Tatsuro Murano, Jakob Begun, Leigh A. Baxt, Gautam Goel, Eduardo J. Villablanca, Szu Yu Kuo, Hailiang Huang, Laurence Macia, Atul K. Bhan, Marcel Batten, Mark J. Daly, Fulvio Reggiori, Charles R. Mackay, Ramnik J. Xavier

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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.

Original languageEnglish
Pages (from-to)1392-1405
Number of pages14
JournalImmunity
Volume44
Issue number6
DOIs
Publication statusPublished - 21 Jun 2016

Cite this

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. / Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk. In: Immunity. 2016 ; Vol. 44, No. 6. pp. 1392-1405.
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title = "Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk",
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.",
author = "Lassen, {Kara G.} and McKenzie, {Craig I.} and Muriel Mari and Tatsuro Murano and Jakob Begun and Baxt, {Leigh A.} and Gautam Goel and Villablanca, {Eduardo J.} and Kuo, {Szu Yu} and Hailiang Huang and Laurence Macia and Bhan, {Atul K.} and Marcel Batten and Daly, {Mark J.} and Fulvio Reggiori and Mackay, {Charles R.} and Xavier, {Ramnik J.}",
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doi = "10.1016/j.immuni.2016.05.007",
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Lassen, KG, McKenzie, CI, Mari, M, Murano, T, Begun, J, Baxt, LA, Goel, G, Villablanca, EJ, Kuo, SY, Huang, H, Macia, L, Bhan, AK, Batten, M, Daly, MJ, Reggiori, F, Mackay, CR & Xavier, RJ 2016, 'Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk', Immunity, vol. 44, no. 6, pp. 1392-1405. https://doi.org/10.1016/j.immuni.2016.05.007

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.; Xavier, Ramnik J.

In: Immunity, Vol. 44, No. 6, 21.06.2016, p. 1392-1405.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk

AU - Lassen, Kara G.

AU - McKenzie, Craig I.

AU - Mari, Muriel

AU - Murano, Tatsuro

AU - Begun, Jakob

AU - Baxt, Leigh A.

AU - Goel, Gautam

AU - Villablanca, Eduardo J.

AU - Kuo, Szu Yu

AU - Huang, Hailiang

AU - Macia, Laurence

AU - Bhan, Atul K.

AU - Batten, Marcel

AU - Daly, Mark J.

AU - Reggiori, Fulvio

AU - Mackay, Charles R.

AU - Xavier, Ramnik J.

PY - 2016/6/21

Y1 - 2016/6/21

N2 - 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.

AB - 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.

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