TY - JOUR
T1 - N-glycanase NGLY1 regulates mitochondrial homeostasis and inflammation through NRF1
AU - Yang, Kun
AU - Huang, Ryan
AU - Fujihira, Haruhiko
AU - Suzuki, Tadashi
AU - Yan, Nan
N1 - Funding Information:
This work is supported by UT Southwestern Medical Center Endowed Scholar Award (N. Yan), Grace Science Foundation (N. Yan and T. Suzuki), and Mr. Hiroshi Mikitani (T. Suzuki). The authors declare no competing financial interests.
Funding Information:
We thank Aamir Zuberi (Jackson Labs) for NGLY1 antibody, Beth Levine (UT Southwestern) for mitophagy assay reagents and technical advice, Prashant Mishra (UT Southwestern) for mitochondrial fusion assay advices, and Kevin Lee and Matt Wilsey at Grace Science Foundation for communications and coordination of reagent sharing. This work is supported by UT Southwestern Medical Center Endowed Scholar Award (N. Yan), Grace Science Foundation (N. Yan and T. Suzuki), and Mr. Hiroshi Mikitani (T. Suzuki). The authors declare no competing financial interests. Author contributions: N. Yan and K. Yang conceived of and designed the study. K. Yang performed most experiments and analyzed data. R. Huang assisted with mouse breeding, including crosses between Ngly1 mice and Sting?/?, Mavs?/? and Infar1?/? mice. T. Suzuki and H. Fujihira provided critical reagents and generated the Ngly1-flox mice. N. Yan supervised the study. N. Yan and K. Yang wrote the paper.
Publisher Copyright:
© 2018 Yang et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
PY - 2018/10/1
Y1 - 2018/10/1
N2 - Mutations in the NGLY1 (N-glycanase 1) gene, encoding an evolutionarily conserved deglycosylation enzyme, are associated with a rare congenital disorder leading to global developmental delay and neurological abnormalities. The molecular mechanism of the NGLY1 disease and its function in tissue and immune homeostasis remain unknown. Here, we find that NGLY1-deficient human and mouse cells chronically activate cytosolic nucleic acid-sensing pathways, leading to elevated interferon gene signature. We also find that cellular clearance of damaged mitochondria by mitophagy is impaired in the absence of NGLY1, resulting in severely fragmented mitochondria and activation of cGAS-STING as well as MDA5-MAVS pathways. Furthermore, we show that NGLY1 regulates mitochondrial homeostasis through transcriptional factor NRF1. Remarkably, pharmacological activation of a homologous but nonglycosylated transcriptional factor NRF2 restores mitochondrial homeostasis and suppresses immune gene activation in NGLY1-deficient cells. Together, our findings reveal novel functions of the NGLY1-NRF1 pathway in mitochondrial homeostasis and inflammation and uncover an unexpected therapeutic strategy using pharmacological activators of NRF2 for treating mitochondrial and immune dysregulation.
AB - Mutations in the NGLY1 (N-glycanase 1) gene, encoding an evolutionarily conserved deglycosylation enzyme, are associated with a rare congenital disorder leading to global developmental delay and neurological abnormalities. The molecular mechanism of the NGLY1 disease and its function in tissue and immune homeostasis remain unknown. Here, we find that NGLY1-deficient human and mouse cells chronically activate cytosolic nucleic acid-sensing pathways, leading to elevated interferon gene signature. We also find that cellular clearance of damaged mitochondria by mitophagy is impaired in the absence of NGLY1, resulting in severely fragmented mitochondria and activation of cGAS-STING as well as MDA5-MAVS pathways. Furthermore, we show that NGLY1 regulates mitochondrial homeostasis through transcriptional factor NRF1. Remarkably, pharmacological activation of a homologous but nonglycosylated transcriptional factor NRF2 restores mitochondrial homeostasis and suppresses immune gene activation in NGLY1-deficient cells. Together, our findings reveal novel functions of the NGLY1-NRF1 pathway in mitochondrial homeostasis and inflammation and uncover an unexpected therapeutic strategy using pharmacological activators of NRF2 for treating mitochondrial and immune dysregulation.
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U2 - 10.1084/JEM.20180783
DO - 10.1084/JEM.20180783
M3 - Article
C2 - 30135079
AN - SCOPUS:85054091052
VL - 215
SP - 2600
EP - 2616
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 10
ER -