Natsuko Tamura1, Yasuhiro Maejima1, Takayoshi Matsumura2, Rick B Vega3, Eisuke Amiya2, Yusuke Ito1, Yuka Shiheido-Watanabe1, Takashi Ashikaga1, Issei Komuro2, Daniel P Kelly4, Kenzo Hirao1, Mitsuaki Isobe1,5. 1. Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Japan (N.T., Y.M., Y.I., Y.S.-W., T.A., K.H., M.I.). 2. Department of Cardiovascular Medicine, The University of Tokyo, Japan (T.M., E.A., I.K.). 3. Translational Research Institute for Diabetes and Metabolism, Florida Hospital, Orlando (R.B.V.). 4. Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.P.K.). 5. Sakakibara Heart Institute, Japan Research Promotion Society for Cardiovascular Diseases, Tokyo (M.I.).
Abstract
BACKGROUND: Takayasu arteritis (TAK) is an autoimmune systemic arteritis of unknown pathogenesis. Genome-wide association studies revealed that single-nucleotide polymorphisms in the MLX gene encoding the MLX (Max-like protein X) transcription factor are significantly associated with TAK in Japanese patients. MLX single-nucleotide polymorphism rs665268 is a missense mutation causing the Q139R substitution in the DNA-binding site of MLX. METHODS: To elucidate the hypothesis that the single-nucleotide polymorphism of the MLX gene plays a critical role in the development of TAK, we conducted clinical and laboratory analyses. RESULTS: We show that rs665268 significantly correlated with the severity of TAK, including the number of arterial lesions and morbidity of aortic regurgitation; the latter may be attributed to the fact that MLX mRNA expression was mostly detected in the aortic valve. Furthermore, the Q139R mutation caused structural changes in MLX, which resulted in enhanced formation of a heterodimer with MondoA, upregulation of TXNIP (thioredoxin-interacting protein) expression, and increase in the activity of the NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome and cellular oxidative stress. Furthermore, autophagy, which negatively regulates inflammasome activation, was suppressed by the Q139R mutation in MLX. The MLX-Q139R mutant significantly induced macrophage proliferation and macrophage-endothelium interaction, which was abolished by the treatment with SBI-477, an inhibitor of MondoA nuclear translocation. Our findings suggest that the Q139R substitution in MLX plays a crucial role in the pathogenesis of TAK. CONCLUSIONS: MLX-Q139R mutation plays a crucial role in the pathogenesis of TAK through promoting inflammasome formation.
BACKGROUND:Takayasu arteritis (TAK) is an autoimmune systemic arteritis of unknown pathogenesis. Genome-wide association studies revealed that single-nucleotide polymorphisms in the MLX gene encoding the MLX (Max-like protein X) transcription factor are significantly associated with TAK in Japanese patients. MLX single-nucleotide polymorphism rs665268 is a missense mutation causing the Q139R substitution in the DNA-binding site of MLX. METHODS: To elucidate the hypothesis that the single-nucleotide polymorphism of the MLX gene plays a critical role in the development of TAK, we conducted clinical and laboratory analyses. RESULTS: We show that rs665268 significantly correlated with the severity of TAK, including the number of arterial lesions and morbidity of aortic regurgitation; the latter may be attributed to the fact that MLX mRNA expression was mostly detected in the aortic valve. Furthermore, the Q139R mutation caused structural changes in MLX, which resulted in enhanced formation of a heterodimer with MondoA, upregulation of TXNIP (thioredoxin-interacting protein) expression, and increase in the activity of the NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome and cellular oxidative stress. Furthermore, autophagy, which negatively regulates inflammasome activation, was suppressed by the Q139R mutation in MLX. The MLX-Q139R mutant significantly induced macrophage proliferation and macrophage-endothelium interaction, which was abolished by the treatment with SBI-477, an inhibitor of MondoA nuclear translocation. Our findings suggest that the Q139R substitution in MLX plays a crucial role in the pathogenesis of TAK. CONCLUSIONS:MLX-Q139R mutation plays a crucial role in the pathogenesis of TAK through promoting inflammasome formation.
Authors: Carrie A Stoltzman; Christopher W Peterson; Kevin T Breen; Deborah M Muoio; Andrew N Billin; Donald E Ayer Journal: Proc Natl Acad Sci U S A Date: 2008-05-05 Impact factor: 11.205
Authors: Michael T Forrester; Divya Seth; Alfred Hausladen; Christine E Eyler; Matthew W Foster; Akio Matsumoto; Moran Benhar; Harvey E Marshall; Jonathan S Stamler Journal: J Biol Chem Date: 2009-10-21 Impact factor: 5.157
Authors: John H Stone; Katie Tuckwell; Sophie Dimonaco; Micki Klearman; Martin Aringer; Daniel Blockmans; Elisabeth Brouwer; Maria C Cid; Bhaskar Dasgupta; Juergen Rech; Carlo Salvarani; Georg Schett; Hendrik Schulze-Koops; Robert Spiera; Sebastian H Unizony; Neil Collinson Journal: N Engl J Med Date: 2017-07-27 Impact factor: 91.245
Authors: Patrick A Carroll; Brian W Freie; Pei Feng Cheng; Sivakanthan Kasinathan; Haiwei Gu; Theresa Hedrich; James A Dowdle; Vivek Venkataramani; Vijay Ramani; Xiaoying Wu; Daniel Raftery; Jay Shendure; Donald E Ayer; Charles H Muller; Robert N Eisenman Journal: PLoS Biol Date: 2021-10-20 Impact factor: 9.593