The E3 ubiquitin ligase SMURF2 stabilizes RNA editase ADAR1p110 and promotes its adenosine-to-inosine (A-to-I) editing function.

Autor: Koganti P; Laboratory of Molecular and Cellular Cancer Biology, Azrieli Faculty of Medicine, Bar-Ilan University, 1311502, Safed, Israel., Kadali VN; Laboratory of Molecular and Cellular Cancer Biology, Azrieli Faculty of Medicine, Bar-Ilan University, 1311502, Safed, Israel., Manikoth Ayyathan D; Laboratory of Molecular and Cellular Cancer Biology, Azrieli Faculty of Medicine, Bar-Ilan University, 1311502, Safed, Israel., Emanuelli A; Laboratory of Molecular and Cellular Cancer Biology, Azrieli Faculty of Medicine, Bar-Ilan University, 1311502, Safed, Israel., Paolini B; Department of Pathology and Laboratory Medicine, IRCCS Fondazione, Istituto Nazionale dei Tumori, Milan, Italy., Levy-Cohen G; Laboratory of Molecular and Cellular Cancer Biology, Azrieli Faculty of Medicine, Bar-Ilan University, 1311502, Safed, Israel., Blank M; Laboratory of Molecular and Cellular Cancer Biology, Azrieli Faculty of Medicine, Bar-Ilan University, 1311502, Safed, Israel. michael.blank@biu.ac.il.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2022 Apr 11; Vol. 79 (5), pp. 237. Date of Electronic Publication: 2022 Apr 11.
DOI: 10.1007/s00018-022-04272-8
Abstrakt: Epitranscriptomic changes in RNA catalyzed by the RNA-editing enzyme ADAR1 play an essential role in the regulation of diverse molecular and cellular processes, both under physiological conditions and in disease states, including cancer. Yet, despite a growing body of evidence pointing to ADAR1 as a potential therapeutic target, the mechanisms regulating its cellular abundance and activity, particularly of its constitutively expressed and ubiquitous form, ADAR1p110, are poorly understood. Here, we report the HECT-type E3 ubiquitin ligase SMURF2 as a pivotal regulator of ADAR1p110. We show that SMURF2, which is primarily known to promote the ubiquitin-mediated degradation of its protein substrates, protects ADAR1p110 from proteolysis and promotes its A-to-I editase activity in human and mouse cells and tissues. ADAR1p110's interactome analysis performed in human cells also showed a positive influence of SMURF2 on the stability and function of ADAR1p110. Mechanistically, we found that SMURF2 directly binds, ubiquitinates and stabilizes ADAR1p110 in an E3 ubiquitin ligase-dependent manner, through ADAR1p110 ubiquitination at lysine-744 (K744). Mutation of this residue to arginine (K744R), which is also associated with several human disorders, including dyschromatosis symmetrica hereditaria (DSH) and some types of cancer, abolished SMURF2-mediated protection of ADAR1p110 from both proteasomal and lysosomal degradation and inactivated ADAR1p110-mediated RNA editing. Our findings reveal a novel mechanism underlying the regulation of ADAR1 in mammalian cells and suggest SMURF2 as a key cellular factor influencing the protein abundance, interactions and functions of ADAR1p110.
(© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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