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BIBTEX RIS

ADAR regulates APOL1 via A-to-I RNA editing by inhibition of MDA5 activation in a paradoxical biological circuit

2022; National Academy of Sciences; Volume: 119; Issue: 44 Linguagem: Inglês

10.1073/pnas.2210150119

1091-6490

Cristian V. Riella, Michelle Mcnulty, Guilherme T. Ribas, Calum F. Tattersfield, Chandra Perez-Gill, Felix Eichinger, Jessica Kelly, Justin Chun, Balajikarthick Subramanian, Dieval Guizelini, Seth L. Alper, Martin R. Pollak, Matthew G. Sampson, David J. Friedman, S Massengill, Katherine M. Dell, John R. Sedor, Berta Martín, Kevin V. Lemley, Shishir Sharma, Tarak Srivastava, Kästner Markus, Christine B. Sethna, Sandro Vento, Pietro A. Canetta, Akshyaya Pradhan, Laurence Greenbaum, Wang Cs, Eun Joo Yun, Sharon G. Adler, Janine LaPage, Meredith A. Atkinson, M. J. Williams, Elizabeth McCarthy, Fernando C. Fervenza, Marie C. Hogan, John C. Lieske, David T. Selewski, C Conley, Frederick J. Kaskel, Michael D. Ross, P. Flynn, Jeffrey B. Kopp, Laura Málaga-Diéguez, Olga Zhdanova, B Pace, Salem Almaani, Richard A. Lafayette, S Dave, Ike Lee, S. Quinn-Boyle, Shrijal S. Shah, Heather N. Reich, Michelle Hladunewich, P. Ling, Martin Romano, P Brakeman, A Podoll, Alessia Fornoni, Carlos Bidot, Matthias Kretzler, Debbie S. Gipson, Amanda Williams, Catherine Klida, Vimal K. Derebail, Keisha L. Gibson, Anne Froment, F Ochoa-Toro, Lawrence B. Holzman, Kevin Meyers, K. Kallem, Andrea Swenson, Kulbhushan Sharma, Kamal Sambandam, Z Wang, M. Rogers, A. Jefferson, Sangeeta Hingorani, Katherine R. Tuttle, L Manahan, Emily Pao, K Kuykendall K, JJ Lin, Stefanie Baker, V Dharnidharka,

CRISPR and Genetic Engineering

APOL1 risk variants are associated with increased risk of kidney disease in patients of African ancestry, but not all individuals with the APOL1 high-risk genotype develop kidney disease. As APOL1 gene expression correlates closely with the degree of kidney cell injury in both cell and animal models, the mechanisms regulating APOL1 expression may be critical determinants of risk allele penetrance. The APOL1 messenger RNA includes Alu elements at the 3′ untranslated region that can form a double-stranded RNA structure (Alu-dsRNA) susceptible to posttranscriptional adenosine deaminase acting on RNA (ADAR)–mediated adenosine-to-inosine (A-to-I) editing, potentially impacting gene expression. We studied the effects of ADAR expression and A-to-I editing on APOL1 levels in podocytes, human kidney tissue, and a transgenic APOL1 mouse model. In interferon-γ (IFN-γ)–stimulated human podocytes, ADAR down-regulates APOL1 by preventing melanoma differentiation-associated protein 5 (MDA5) recognition of dsRNA and the subsequent type I interferon (IFN-I) response. Knockdown experiments showed that recognition of APOL1 messenger RNA itself is an important contributor to the MDA5-driven IFN-I response. Mathematical modeling suggests that the IFN–ADAR–APOL1 network functions as an incoherent feed-forward loop, a biological circuit capable of generating fast, transient responses to stimuli. Glomeruli from human kidney biopsies exhibited widespread editing of APOL1 Alu-dsRNA, while the transgenic mouse model closely replicated the edited sites in humans. APOL1 expression in mice was inversely correlated with Adar1 expression under IFN-γ stimuli, supporting the idea that ADAR regulates APOL1 levels in vivo. ADAR-mediated A-to-I editing is an important regulator of APOL1 expression that could impact both penetrance and severity of APOL1-associated kidney disease.