TY - JOUR
T1 - Noncanonical role for Ku70/80 in the prevention of allergic airway inflammation via maintenance of airway epithelial cell organelle homeostasis
AU - Rehman, Rakhshinda
AU - Vijayakumar, Vijay Elakkya
AU - Jaiswal, Ashish
AU - Jain, X. Vaibhav
AU - Mukherjee, Shravani
AU - Vellarikkal, X. Shamsudheen Karuthedath
AU - Dieffenbach, Paul B.
AU - Fredenburgh, Laura E.
AU - Prakash, X. Y.S.
AU - Ghosh, Balaram
AU - Agrawal, Anurag
AU - Mabalirajan, Ulaganathan
N1 - Funding Information:
This work was supported by Projects MLP137 (MISSION LUNG), MLP 5502, MLP 126 (CSIR, Govt. of India), GAP 0118 (Dept. of Biotechnology, Govt. of India) and GAP 0084 (Dept. of Science and Technology, Govt. of India) at Institute of Genomics and Integrative Biology and the Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Govt. of India. L. E. Fredenburgh reports grants from NIH/NHLBI, Department of Defense, and American Heart Association outside the submitted work.
Publisher Copyright:
Copyright © 2020 the American Physiological Society.
PY - 2020/10/6
Y1 - 2020/10/6
N2 - Airway epithelial homeostasis is under constant threat due to continuous exposure to the external environment, and abnormally robust sensitivity to external stimuli is critical to the development of airway diseases, including asthma. Ku is a key nonhomologous end-joining DNA repair protein with diverse cellular functions such as VDJ recombination and telomere length maintenance. Here, we show a novel function of Ku in alleviating features of allergic airway inflammation via the regulation of mitochondrial and endoplasmic reticulum (ER) stress. We first determined that airway epithelial cells derived from both asthmatic lungs and murine asthma models demonstrate increased expression of 8-hydroxy-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. Ku protein expression was dramatically reduced in the bronchial epithelium of patients with asthma as well as in human bronchial epithelial cells exposed to oxidative stress. Knockdown of Ku70 or Ku80 in naïve mice elicited mitochondrial collapse or ER stress, leading to bronchial epithelial cell apoptosis and spontaneous development of asthma-like features, including airway hyperresponsiveness, airway inflammation, and subepithelial fibrosis. These findings demonstrate an essential noncanonical role for Ku proteins in asthma pathogenesis, likely via maintenance of organelle homeostasis. This novel function of Ku proteins may also be important in other disease processes associated with organelle stress.
AB - Airway epithelial homeostasis is under constant threat due to continuous exposure to the external environment, and abnormally robust sensitivity to external stimuli is critical to the development of airway diseases, including asthma. Ku is a key nonhomologous end-joining DNA repair protein with diverse cellular functions such as VDJ recombination and telomere length maintenance. Here, we show a novel function of Ku in alleviating features of allergic airway inflammation via the regulation of mitochondrial and endoplasmic reticulum (ER) stress. We first determined that airway epithelial cells derived from both asthmatic lungs and murine asthma models demonstrate increased expression of 8-hydroxy-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. Ku protein expression was dramatically reduced in the bronchial epithelium of patients with asthma as well as in human bronchial epithelial cells exposed to oxidative stress. Knockdown of Ku70 or Ku80 in naïve mice elicited mitochondrial collapse or ER stress, leading to bronchial epithelial cell apoptosis and spontaneous development of asthma-like features, including airway hyperresponsiveness, airway inflammation, and subepithelial fibrosis. These findings demonstrate an essential noncanonical role for Ku proteins in asthma pathogenesis, likely via maintenance of organelle homeostasis. This novel function of Ku proteins may also be important in other disease processes associated with organelle stress.
KW - Airway epithelium
KW - Asthma
KW - Ku
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U2 - 10.1152/AJPLUNG.00522.2019
DO - 10.1152/AJPLUNG.00522.2019
M3 - Article
C2 - 32877223
AN - SCOPUS:85092682258
VL - 319
SP - L728-L741
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 1040-0605
IS - 4
ER -