K63-linked ubiquitylation induces global sequestration of mitochondria

Abstract Even though K63-linked polyubiquitin chains do not target proteins for proteasomal degradation, they play nevertheless a complementary protective role in maintaining protein homeostasis by directing malfunctioning proteins and organelles to inclusion bodies or autophagosomes. A paradigm for...

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Autores principales:	Thibaud J. C. Richard, Laura K. Herzog, Julia Vornberger, Aldwin Suryo Rahmanto, Olle Sangfelt, Florian A. Salomons, Nico P. Dantuma
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c16e088089de40dbade83e4e69e958b1
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spelling	oai:doaj.org-article:c16e088089de40dbade83e4e69e958b12021-12-02T13:34:01ZK63-linked ubiquitylation induces global sequestration of mitochondria10.1038/s41598-020-78845-72045-2322https://doaj.org/article/c16e088089de40dbade83e4e69e958b12020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78845-7https://doaj.org/toc/2045-2322Abstract Even though K63-linked polyubiquitin chains do not target proteins for proteasomal degradation, they play nevertheless a complementary protective role in maintaining protein homeostasis by directing malfunctioning proteins and organelles to inclusion bodies or autophagosomes. A paradigm for this process is the sequestration and autophagic degradation of dysfunctional mitochondria. Although studies have shown that K63-ubiquitylation of mitochondrial proteins by the ubiquitin ligase Parkin is important in this process, it is presently not clear if this modification also suffices to initiate this cascade of events. To address this question, we have engineered the ubiquitin ligase ProxE3, which in an inducible manner synthesizes K63-linked ubiquitin chains on the surface of mitochondria. We found that the presence of K63-linked ubiquitin chains on mitochondria resulted in the recruitment of the ubiquitin adaptor p62 and induced a dramatic redistribution of mitochondria, which was reminiscent to the Parkin-facilitated sequestration in response to mitochondrial uncoupler. However, ProxE3 did not induce autophagic degradation of mitochondria. Our data show that K63-linked ubiquitin chains at the mitochondrial membrane are sufficient for the induction of mitochondrial sequestration, but not mitophagy, without the need of extrinsically inflicting mitochondrial dysfunction.Thibaud J. C. RichardLaura K. HerzogJulia VornbergerAldwin Suryo RahmantoOlle SangfeltFlorian A. SalomonsNico P. DantumaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thibaud J. C. Richard Laura K. Herzog Julia Vornberger Aldwin Suryo Rahmanto Olle Sangfelt Florian A. Salomons Nico P. Dantuma K63-linked ubiquitylation induces global sequestration of mitochondria
description	Abstract Even though K63-linked polyubiquitin chains do not target proteins for proteasomal degradation, they play nevertheless a complementary protective role in maintaining protein homeostasis by directing malfunctioning proteins and organelles to inclusion bodies or autophagosomes. A paradigm for this process is the sequestration and autophagic degradation of dysfunctional mitochondria. Although studies have shown that K63-ubiquitylation of mitochondrial proteins by the ubiquitin ligase Parkin is important in this process, it is presently not clear if this modification also suffices to initiate this cascade of events. To address this question, we have engineered the ubiquitin ligase ProxE3, which in an inducible manner synthesizes K63-linked ubiquitin chains on the surface of mitochondria. We found that the presence of K63-linked ubiquitin chains on mitochondria resulted in the recruitment of the ubiquitin adaptor p62 and induced a dramatic redistribution of mitochondria, which was reminiscent to the Parkin-facilitated sequestration in response to mitochondrial uncoupler. However, ProxE3 did not induce autophagic degradation of mitochondria. Our data show that K63-linked ubiquitin chains at the mitochondrial membrane are sufficient for the induction of mitochondrial sequestration, but not mitophagy, without the need of extrinsically inflicting mitochondrial dysfunction.
format	article
author	Thibaud J. C. Richard Laura K. Herzog Julia Vornberger Aldwin Suryo Rahmanto Olle Sangfelt Florian A. Salomons Nico P. Dantuma
author_facet	Thibaud J. C. Richard Laura K. Herzog Julia Vornberger Aldwin Suryo Rahmanto Olle Sangfelt Florian A. Salomons Nico P. Dantuma
author_sort	Thibaud J. C. Richard
title	K63-linked ubiquitylation induces global sequestration of mitochondria
title_short	K63-linked ubiquitylation induces global sequestration of mitochondria
title_full	K63-linked ubiquitylation induces global sequestration of mitochondria
title_fullStr	K63-linked ubiquitylation induces global sequestration of mitochondria
title_full_unstemmed	K63-linked ubiquitylation induces global sequestration of mitochondria
title_sort	k63-linked ubiquitylation induces global sequestration of mitochondria
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/c16e088089de40dbade83e4e69e958b1
work_keys_str_mv	AT thibaudjcrichard k63linkedubiquitylationinducesglobalsequestrationofmitochondria AT laurakherzog k63linkedubiquitylationinducesglobalsequestrationofmitochondria AT juliavornberger k63linkedubiquitylationinducesglobalsequestrationofmitochondria AT aldwinsuryorahmanto k63linkedubiquitylationinducesglobalsequestrationofmitochondria AT ollesangfelt k63linkedubiquitylationinducesglobalsequestrationofmitochondria AT florianasalomons k63linkedubiquitylationinducesglobalsequestrationofmitochondria AT nicopdantuma k63linkedubiquitylationinducesglobalsequestrationofmitochondria
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K63-linked ubiquitylation induces global sequestration of mitochondria

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