Loss-of-Function Piezo1 Mutations Display Altered Stability Driven by Ubiquitination and Proteasomal Degradation

Missense mutations in the gene that encodes for the mechanically-gated ion channel Piezo1 have been linked to a number of diseases. Gain-of-function variants are linked to a hereditary anaemia and loss-of-function variants have been linked to generalized lymphatic dysplasia and bicuspid aortic valve...

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Autores principales:	Zijing Zhou, Jinyuan Vero Li, Boris Martinac, Charles D. Cox
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	post-translational modification (PMT) protein biosynthesis mechanosensation ubiquitiantion proteasomal degradation Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/fbea43c946d1477daeeae839dbfebaee
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spelling	oai:doaj.org-article:fbea43c946d1477daeeae839dbfebaee2021-11-19T07:08:36ZLoss-of-Function Piezo1 Mutations Display Altered Stability Driven by Ubiquitination and Proteasomal Degradation1663-981210.3389/fphar.2021.766416https://doaj.org/article/fbea43c946d1477daeeae839dbfebaee2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.766416/fullhttps://doaj.org/toc/1663-9812Missense mutations in the gene that encodes for the mechanically-gated ion channel Piezo1 have been linked to a number of diseases. Gain-of-function variants are linked to a hereditary anaemia and loss-of-function variants have been linked to generalized lymphatic dysplasia and bicuspid aortic valve. Two previously characterized mutations, S217L and G2029R, both exhibit reduced plasma membrane trafficking. Here we show that both mutations also display reduced stability and higher turnover rates than wild-type Piezo1 channels. This occurs through increased ubiquitination and subsequent proteasomal degradation. Congruent with this, proteasome inhibition using N-acetyl-l-leucyl-l-leucyl-l-norleucinal (ALLN) reduced the degradation of both mutant proteins. While ALLN treatment could not rescue the function of S217L we show via multiple complementary methodologies that proteasome inhibition via ALLN treatment can not only prevent G2029R turnover but increase the membrane localized pool of this variant and the functional Piezo1 mechanosensitive currents. This data in combination with a precision medicine approach provides a new potential therapeutic avenue for the treatment of Piezo1 mediated channelopathies.Zijing ZhouJinyuan Vero LiBoris MartinacBoris MartinacCharles D. CoxCharles D. CoxFrontiers Media S.A.articlepost-translational modification (PMT)protein biosynthesismechanosensationubiquitiantionproteasomal degradationTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	post-translational modification (PMT) protein biosynthesis mechanosensation ubiquitiantion proteasomal degradation Therapeutics. Pharmacology RM1-950
spellingShingle	post-translational modification (PMT) protein biosynthesis mechanosensation ubiquitiantion proteasomal degradation Therapeutics. Pharmacology RM1-950 Zijing Zhou Jinyuan Vero Li Boris Martinac Boris Martinac Charles D. Cox Charles D. Cox Loss-of-Function Piezo1 Mutations Display Altered Stability Driven by Ubiquitination and Proteasomal Degradation
description	Missense mutations in the gene that encodes for the mechanically-gated ion channel Piezo1 have been linked to a number of diseases. Gain-of-function variants are linked to a hereditary anaemia and loss-of-function variants have been linked to generalized lymphatic dysplasia and bicuspid aortic valve. Two previously characterized mutations, S217L and G2029R, both exhibit reduced plasma membrane trafficking. Here we show that both mutations also display reduced stability and higher turnover rates than wild-type Piezo1 channels. This occurs through increased ubiquitination and subsequent proteasomal degradation. Congruent with this, proteasome inhibition using N-acetyl-l-leucyl-l-leucyl-l-norleucinal (ALLN) reduced the degradation of both mutant proteins. While ALLN treatment could not rescue the function of S217L we show via multiple complementary methodologies that proteasome inhibition via ALLN treatment can not only prevent G2029R turnover but increase the membrane localized pool of this variant and the functional Piezo1 mechanosensitive currents. This data in combination with a precision medicine approach provides a new potential therapeutic avenue for the treatment of Piezo1 mediated channelopathies.
format	article
author	Zijing Zhou Jinyuan Vero Li Boris Martinac Boris Martinac Charles D. Cox Charles D. Cox
author_facet	Zijing Zhou Jinyuan Vero Li Boris Martinac Boris Martinac Charles D. Cox Charles D. Cox
author_sort	Zijing Zhou
title	Loss-of-Function Piezo1 Mutations Display Altered Stability Driven by Ubiquitination and Proteasomal Degradation
title_short	Loss-of-Function Piezo1 Mutations Display Altered Stability Driven by Ubiquitination and Proteasomal Degradation
title_full	Loss-of-Function Piezo1 Mutations Display Altered Stability Driven by Ubiquitination and Proteasomal Degradation
title_fullStr	Loss-of-Function Piezo1 Mutations Display Altered Stability Driven by Ubiquitination and Proteasomal Degradation
title_full_unstemmed	Loss-of-Function Piezo1 Mutations Display Altered Stability Driven by Ubiquitination and Proteasomal Degradation
title_sort	loss-of-function piezo1 mutations display altered stability driven by ubiquitination and proteasomal degradation
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/fbea43c946d1477daeeae839dbfebaee
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Loss-of-Function Piezo1 Mutations Display Altered Stability Driven by Ubiquitination and Proteasomal Degradation

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