VCP/p97 modulates PtdIns3P production and autophagy initiation

Lidia Wrobel; Sandra M. Hill; Avraham Ashkenazi; David C. Rubinsztein

doi:10.1080/15548627.2021.1898742

VCP/p97 modulates PtdIns3P production and autophagy initiation

Lidia Wrobel, Sandra M. Hill, Avraham Ashkenazi, David C. Rubinsztein

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

VCP/p97 is an essential multifunctional protein implicated in a plethora of intracellular quality control systems, and abnormal function of VCP is the underlying cause of several neurodegenerative disorders. We reported that VCP regulates the levels of the macroautophagy/autophagy-inducing lipid phosphatidylinositol-3-phosphate (PtdIns3P) by modulating the activity of the BECN1 (beclin 1)-containing phosphatidylinositol 3-kinase (PtdIns3K) complex. VCP stimulates the deubiquitinase activity of ATXN3 (ataxin 3) to stabilize BECN1 protein levels and also interacts with and promotes the assembly and kinase activity of the PtdIns3K complex. Acute inhibition of VCP activity impairs autophagy induction, demonstrated by a diminished PtdIns3P production and decreased recruitment of early autophagy markers WIPI2 and ATG16L1. Thus, VCP promotes autophagosome biogenesis, in addition to its previously described role in autophagosome maturation.

Original language	English
Pages (from-to)	1052-1053
Number of pages	2
Journal	Autophagy
Volume	17
Issue number	4
DOIs	https://doi.org/10.1080/15548627.2021.1898742
State	Published - 1 Jan 2021
Externally published	Yes

Keywords

ATXN3
PI(3)P
PI3K
VCP/p97
autophagy initiation
beclin 1

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1080/15548627.2021.1898742

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title = "VCP/p97 modulates PtdIns3P production and autophagy initiation",

abstract = "VCP/p97 is an essential multifunctional protein implicated in a plethora of intracellular quality control systems, and abnormal function of VCP is the underlying cause of several neurodegenerative disorders. We reported that VCP regulates the levels of the macroautophagy/autophagy-inducing lipid phosphatidylinositol-3-phosphate (PtdIns3P) by modulating the activity of the BECN1 (beclin 1)-containing phosphatidylinositol 3-kinase (PtdIns3K) complex. VCP stimulates the deubiquitinase activity of ATXN3 (ataxin 3) to stabilize BECN1 protein levels and also interacts with and promotes the assembly and kinase activity of the PtdIns3K complex. Acute inhibition of VCP activity impairs autophagy induction, demonstrated by a diminished PtdIns3P production and decreased recruitment of early autophagy markers WIPI2 and ATG16L1. Thus, VCP promotes autophagosome biogenesis, in addition to its previously described role in autophagosome maturation.",

keywords = "ATXN3, PI(3)P, PI3K, VCP/p97, autophagy initiation, beclin 1",

author = "Lidia Wrobel and Hill, {Sandra M.} and Avraham Ashkenazi and Rubinsztein, {David C.}",

note = "Publisher Copyright: {\textcopyright} 2021 Informa UK Limited, trading as Taylor & Francis Group.",

year = "2021",

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AU - Wrobel, Lidia

AU - Hill, Sandra M.

AU - Ashkenazi, Avraham

AU - Rubinsztein, David C.

PY - 2021/1/1

Y1 - 2021/1/1

N2 - VCP/p97 is an essential multifunctional protein implicated in a plethora of intracellular quality control systems, and abnormal function of VCP is the underlying cause of several neurodegenerative disorders. We reported that VCP regulates the levels of the macroautophagy/autophagy-inducing lipid phosphatidylinositol-3-phosphate (PtdIns3P) by modulating the activity of the BECN1 (beclin 1)-containing phosphatidylinositol 3-kinase (PtdIns3K) complex. VCP stimulates the deubiquitinase activity of ATXN3 (ataxin 3) to stabilize BECN1 protein levels and also interacts with and promotes the assembly and kinase activity of the PtdIns3K complex. Acute inhibition of VCP activity impairs autophagy induction, demonstrated by a diminished PtdIns3P production and decreased recruitment of early autophagy markers WIPI2 and ATG16L1. Thus, VCP promotes autophagosome biogenesis, in addition to its previously described role in autophagosome maturation.

AB - VCP/p97 is an essential multifunctional protein implicated in a plethora of intracellular quality control systems, and abnormal function of VCP is the underlying cause of several neurodegenerative disorders. We reported that VCP regulates the levels of the macroautophagy/autophagy-inducing lipid phosphatidylinositol-3-phosphate (PtdIns3P) by modulating the activity of the BECN1 (beclin 1)-containing phosphatidylinositol 3-kinase (PtdIns3K) complex. VCP stimulates the deubiquitinase activity of ATXN3 (ataxin 3) to stabilize BECN1 protein levels and also interacts with and promotes the assembly and kinase activity of the PtdIns3K complex. Acute inhibition of VCP activity impairs autophagy induction, demonstrated by a diminished PtdIns3P production and decreased recruitment of early autophagy markers WIPI2 and ATG16L1. Thus, VCP promotes autophagosome biogenesis, in addition to its previously described role in autophagosome maturation.

KW - ATXN3

KW - PI(3)P

KW - PI3K

KW - VCP/p97

KW - autophagy initiation

KW - beclin 1

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U2 - 10.1080/15548627.2021.1898742

DO - 10.1080/15548627.2021.1898742

M3 - Article

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AN - SCOPUS:85102523634

SN - 1554-8627

VL - 17

SP - 1052

EP - 1053

JO - Autophagy

JF - Autophagy

IS - 4

ER -

VCP/p97 modulates PtdIns3P production and autophagy initiation

Abstract

Keywords

ASJC Scopus subject areas

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