IKBKB reduces huntingtin aggregation by phosphorylating serine 13 via a non-canonical IKK pathway.

Autor:	Cariulo C; Neuroscience Unit, Translational and Discovery Research Department, IRBM S.p.A., Rome, Italy c.cariulo@irbm.com., Martufi P; Neuroscience Unit, Translational and Discovery Research Department, IRBM S.p.A., Rome, Italy., Verani M; Neuroscience Unit, Translational and Discovery Research Department, IRBM S.p.A., Rome, Italy., Toledo-Sherman L; Rainwatercf.org Tau Consortium, Rainwater Charitable Foundation, Fort Worth, TX, USA.; UCLA, Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA., Lee R; CHDI Management/CHDI Foundation, Princeton, NJ, USA ramee.lee@chdifoundation.org., Dominguez C; CHDI Management/CHDI Foundation, Princeton, NJ, USA., Petricca L; Neuroscience Unit, Translational and Discovery Research Department, IRBM S.p.A., Rome, Italy., Caricasole A; Neuroscience Unit, Translational and Discovery Research Department, IRBM S.p.A., Rome, Italy.
Jazyk:	angličtina
Zdroj:	Life science alliance [Life Sci Alliance] 2023 Aug 08; Vol. 6 (10). Date of Electronic Publication: 2023 Aug 08 (Print Publication: 2023).
DOI:	10.26508/lsa.202302006
Abstrakt:	N-terminal phosphorylation at residues T3 and S13 is believed to have important beneficial implications for the biological and pathological properties of mutant huntingtin, where inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB) was identified as a candidate regulator of huntingtin N-terminal phosphorylation. The paucity of mechanistic information on IKK pathways, together with the lack of sensitive methods to quantify endogenous huntingtin phosphorylation, prevented detailed study of the role of IKBKB in Huntington's disease. Using novel ultrasensitive assays, we demonstrate that IKBKB can regulate endogenous S13 huntingtin phosphorylation in a manner, dependent on its kinase activity and known regulators. We found that the ability of IKBKB to phosphorylate endogenous huntingtin S13 is mediated through a non-canonical interferon regulatory factor3-mediated IKK pathway, distinct from the established involvement of IKBKB in mutant huntingtin's pathological mechanisms mediated via the canonical pathway. Furthermore, increased huntingtin S13 phosphorylation by IKBKB resulted in decreased aggregation of mutant huntingtin in cells, again dependent on its kinase activity. These findings point to a non-canonical IKK pathway linking S13 huntingtin phosphorylation to the pathological properties of mutant huntingtin aggregation, thought to be significant to Huntington's disease. (© 2023 Cariulo et al.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu