The diabetes susceptibility gene clec16a regulates mitophagy.
(2014) In Cell 157(7). p.1577-1590- Abstract
- Clec16a has been identified as a disease susceptibility gene for type 1 diabetes, multiple sclerosis, and adrenal dysfunction, but its function is unknown. Here we report that Clec16a is a membrane-associated endosomal protein that interacts with E3 ubiquitin ligase Nrdp1. Loss of Clec16a leads to an increase in the Nrdp1 target Parkin, a master regulator of mitophagy. Islets from mice with pancreas-specific deletion of Clec16a have abnormal mitochondria with reduced oxygen consumption and ATP concentration, both of which are required for normal β cell function. Indeed, pancreatic Clec16a is required for normal glucose-stimulated insulin release. Moreover, patients harboring a diabetogenic SNP in the Clec16a gene have reduced islet Clec16a... (More)
- Clec16a has been identified as a disease susceptibility gene for type 1 diabetes, multiple sclerosis, and adrenal dysfunction, but its function is unknown. Here we report that Clec16a is a membrane-associated endosomal protein that interacts with E3 ubiquitin ligase Nrdp1. Loss of Clec16a leads to an increase in the Nrdp1 target Parkin, a master regulator of mitophagy. Islets from mice with pancreas-specific deletion of Clec16a have abnormal mitochondria with reduced oxygen consumption and ATP concentration, both of which are required for normal β cell function. Indeed, pancreatic Clec16a is required for normal glucose-stimulated insulin release. Moreover, patients harboring a diabetogenic SNP in the Clec16a gene have reduced islet Clec16a expression and reduced insulin secretion. Thus, Clec16a controls β cell function and prevents diabetes by controlling mitophagy. This pathway could be targeted for prevention and control of diabetes and may extend to the pathogenesis of other Clec16a- and Parkin-associated diseases. (Less)
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https://lup.lub.lu.se/record/4527439
- author
- organization
- publishing date
- 2014
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cell
- volume
- 157
- issue
- 7
- pages
- 1577 - 1590
- publisher
- Cell Press
- external identifiers
-
- pmid:24949970
- wos:000340941900013
- scopus:84903196141
- pmid:24949970
- ISSN
- 1097-4172
- DOI
- 10.1016/j.cell.2014.05.016
- language
- English
- LU publication?
- yes
- id
- 4ef0dfda-149c-4c11-a153-c81111226361 (old id 4527439)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/24949970?dopt=Abstract
- date added to LUP
- 2016-04-01 09:56:05
- date last changed
- 2024-05-05 22:54:08
@article{4ef0dfda-149c-4c11-a153-c81111226361, abstract = {{Clec16a has been identified as a disease susceptibility gene for type 1 diabetes, multiple sclerosis, and adrenal dysfunction, but its function is unknown. Here we report that Clec16a is a membrane-associated endosomal protein that interacts with E3 ubiquitin ligase Nrdp1. Loss of Clec16a leads to an increase in the Nrdp1 target Parkin, a master regulator of mitophagy. Islets from mice with pancreas-specific deletion of Clec16a have abnormal mitochondria with reduced oxygen consumption and ATP concentration, both of which are required for normal β cell function. Indeed, pancreatic Clec16a is required for normal glucose-stimulated insulin release. Moreover, patients harboring a diabetogenic SNP in the Clec16a gene have reduced islet Clec16a expression and reduced insulin secretion. Thus, Clec16a controls β cell function and prevents diabetes by controlling mitophagy. This pathway could be targeted for prevention and control of diabetes and may extend to the pathogenesis of other Clec16a- and Parkin-associated diseases.}}, author = {{Soleimanpour, Scott A and Gupta, Aditi and Bakay, Marina and Ferrari, Alana M and Groff, David N and Fadista, Joao and Spruce, Lynn A and Kushner, Jake A and Groop, Leif and Seeholzer, Steven H and Kaufman, Brett A and Hakonarson, Hakon and Stoffers, Doris A}}, issn = {{1097-4172}}, language = {{eng}}, number = {{7}}, pages = {{1577--1590}}, publisher = {{Cell Press}}, series = {{Cell}}, title = {{The diabetes susceptibility gene clec16a regulates mitophagy.}}, url = {{http://dx.doi.org/10.1016/j.cell.2014.05.016}}, doi = {{10.1016/j.cell.2014.05.016}}, volume = {{157}}, year = {{2014}}, }