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

• DOI: 10.1073/pnas.2210150119
• Publication Date: 2022-10-25T17:56:17Z
• Authors: Cristian V. Riella; Michelle McNulty; Guilherme T. Ribas; Calum F. Tattersf...; Chandra Perez-Gill; Felix Eichinger; Jessica Kelly; Justin Chun; Balajikarthick Su...; Dieval Guizelini; ; Seth L. Alper; Martin R. Pollak; Matthew G. Sampson; David J. Friedman; S Massengill; K Dell; J Sedor; B Martin; K Lemley; S Sharma; T Srivastava; K Markus; C Sethna; S Vento; P Canetta; A Pradhan; L Greenbaum; CS Wang; E Yun; S Adler; J LaPage; M Atkinson; M Williams; E McCarthy; F Fervenza; M Hogan; J Lieske; D Selewski; C Conley; F Kaskel; M Ross; P Flynn; J Kopp; L Malaga-Dieguez; O Zhdanova; B Pace; S Almaani; R Lafayette; S Dave; I Lee; S Quinn-Boyle; S Shah; H Reich; M Hladunewich; P Ling; M Romano; P Brakeman; A Podoll; A Fornoni; C Bidot; M Kretzler; D Gipson; A Williams; C Klida; V Derebail; K Gibson; A Froment; F Ochoa-Toro; L Holzman; K Meyers; K Kallem; A Swenson; K Sharma; K Sambandam; Z Wang; M Rogers; A Jefferson; S Hingorani; K Tuttle; L Manahan; E Pao; K Kuykendall K; JJ Lin; Stefanie Baker; V Dharnidharka
• Keywords: ADAR; MDA5; RNA Silencing

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