NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity

Jiahong Lu; Liqiang He; Christian Behrends; Masatake Araki; Kimi Araki; Qing Jun Wang; Joseph M. Catanzaro; Scott L. Friedman; Wei Xing Zong; M. Isabel Fiel; Min Li; Zhenyu Yue

doi:10.1038/ncomms4920

NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity

Jiahong Lu
, Liqiang He
, Christian Behrends
, Masatake Araki
, Kimi Araki
, Qing Jun Wang
, Joseph M. Catanzaro
, Scott L. Friedman
, Wei Xing Zong
, M. Isabel Fiel
, Min Li
, Zhenyu Yue

Opthalmology

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

120 Scopus citations

Abstract

The Beclin 1-Vps34 complex, the core component of the class III phosphatidylinositol-3 kinase (PI3K-III), binds Atg14L or UVRAG to control different steps of autophagy. However, the mechanism underlying the control of PI3K-III activity remains elusive. Here we report the identification of NRBF2 as a component in the specific PI3K-III complex and a modulator of PI3K-III activity. Through its microtubule interaction and trafficking (MIT) domain, NRBF2 binds Atg14L directly and enhances Atg14L-linked Vps34 kinase activity and autophagy induction. NRBF2-deficient cells exhibit enhanced vulnerability to endoplasmic reticulum (ER) stress that is reversed by re-introducing exogenous NRBF2. NRBF2-deficient mice develop focal liver necrosis and ductular reaction, accompanied by impaired Atg14L-linked Vps34 activity and autophagy, although the mice show no increased mortality. Our data reveal a key role for NRBF2 in the assembly of the specific Atg14L-Beclin 1-Vps34-Vps15 complex for autophagy induction. Thus, NRBF2 modulates autophagy via regulation of PI3K-III and prevents ER stress-mediated cytotoxicity and liver injury.

Original language	English
Article number	3920
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms4920
State	Published - May 22 2014

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health grants (NIH-R01NS060123) to Z.Y. We thank T. Johansen from The University of Tromsø for mCherry–EGFP–LC3B plasmid; J. Jung from University of Southern California for Flag-UVRAG plasmid; K. Kelley from Mount Sinai mouse genetics core facility for help with embryonic stem cells microinjection; R. Huq and L. O’Rourke from Mount Sinai microscopy core facility; W. Janssen from the Mount Sinai Friedman Brain Institute core facility for help with microscopy; and N. McKnight of the Yue lab for critical reading. We thank T.H. Thin from the immunohistochemistry core of the histology shared resource facility and M. Castillo-Martin from the Department of Pathology at Mount Sinai Hospital for their help with mice tissue immunohistochemistry; and Y. Ge from neurology department, N. Shao from neuroscience department of Icahn School of Medicine at Mount Sinai, Q. Lin and Q. Wang from School of public health, Central South University for their assistance with statistical analysis. We specially thank Ms Lorreta Ho for her generous financial support to the postdoctoral fellowship of J.L.

Funding

This work was supported by National Institutes of Health grants (NIH-R01NS060123) to Z.Y. We thank T. Johansen from The University of Troms\u00F8 for mCherry\u2013EGFP\u2013LC3B plasmid; J. Jung from University of Southern California for Flag-UVRAG plasmid; K. Kelley from Mount Sinai mouse genetics core facility for help with embryonic stem cells microinjection; R. Huq and L. O\u2019Rourke from Mount Sinai microscopy core facility; W. Janssen from the Mount Sinai Friedman Brain Institute core facility for help with microscopy; and N. McKnight of the Yue lab for critical reading. We thank T.H. Thin from the immunohistochemistry core of the histology shared resource facility and M. Castillo-Martin from the Department of Pathology at Mount Sinai Hospital for their help with mice tissue immunohistochemistry; and Y. Ge from neurology department, N. Shao from neuroscience department of Icahn School of Medicine at Mount Sinai, Q. Lin and Q. Wang from School of public health, Central South University for their assistance with statistical analysis. We specially thank Ms Lorreta Ho for her generous financial support to the postdoctoral fellowship of J.L.

Funders	Funder number
National Institutes of Health (NIH)
European Commission
National Institute of General Medical Sciences	R01GM097355
National Institute of General Medical Sciences
Seventh Framework Programme	282333
Seventh Framework Programme
Japan Society for the Promotion of Science Fund for the Promotion of Joint International Research	25640052, 23310135
Japan Society for the Promotion of Science Fund for the Promotion of Joint International Research
National Institute on Alcohol Abuse and Alcoholism	R01AA020709
National Institute on Alcohol Abuse and Alcoholism
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	R01NS060123
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council
National Childhood Cancer Registry – National Cancer Institute	R01CA129536
National Childhood Cancer Registry – National Cancer Institute

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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@article{0b21803705724924b8a00f0f003083f2,

title = "NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity",

abstract = "The Beclin 1-Vps34 complex, the core component of the class III phosphatidylinositol-3 kinase (PI3K-III), binds Atg14L or UVRAG to control different steps of autophagy. However, the mechanism underlying the control of PI3K-III activity remains elusive. Here we report the identification of NRBF2 as a component in the specific PI3K-III complex and a modulator of PI3K-III activity. Through its microtubule interaction and trafficking (MIT) domain, NRBF2 binds Atg14L directly and enhances Atg14L-linked Vps34 kinase activity and autophagy induction. NRBF2-deficient cells exhibit enhanced vulnerability to endoplasmic reticulum (ER) stress that is reversed by re-introducing exogenous NRBF2. NRBF2-deficient mice develop focal liver necrosis and ductular reaction, accompanied by impaired Atg14L-linked Vps34 activity and autophagy, although the mice show no increased mortality. Our data reveal a key role for NRBF2 in the assembly of the specific Atg14L-Beclin 1-Vps34-Vps15 complex for autophagy induction. Thus, NRBF2 modulates autophagy via regulation of PI3K-III and prevents ER stress-mediated cytotoxicity and liver injury.",

author = "Jiahong Lu and Liqiang He and Christian Behrends and Masatake Araki and Kimi Araki and \{Jun Wang\}, Qing and Catanzaro, \{Joseph M.\} and Friedman, \{Scott L.\} and Zong, \{Wei Xing\} and Fiel, \{M. Isabel\} and Min Li and Zhenyu Yue",

note = "Funding Information: This work was supported by National Institutes of Health grants (NIH-R01NS060123) to Z.Y. We thank T. Johansen from The University of Troms{\o} for mCherry–EGFP–LC3B plasmid; J. Jung from University of Southern California for Flag-UVRAG plasmid; K. Kelley from Mount Sinai mouse genetics core facility for help with embryonic stem cells microinjection; R. Huq and L. O{\textquoteright}Rourke from Mount Sinai microscopy core facility; W. Janssen from the Mount Sinai Friedman Brain Institute core facility for help with microscopy; and N. McKnight of the Yue lab for critical reading. We thank T.H. Thin from the immunohistochemistry core of the histology shared resource facility and M. Castillo-Martin from the Department of Pathology at Mount Sinai Hospital for their help with mice tissue immunohistochemistry; and Y. Ge from neurology department, N. Shao from neuroscience department of Icahn School of Medicine at Mount Sinai, Q. Lin and Q. Wang from School of public health, Central South University for their assistance with statistical analysis. We specially thank Ms Lorreta Ho for her generous financial support to the postdoctoral fellowship of J.L.",

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doi = "10.1038/ncomms4920",

language = "English",

volume = "5",

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T1 - NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity

AU - Lu, Jiahong

AU - He, Liqiang

AU - Behrends, Christian

AU - Araki, Masatake

AU - Araki, Kimi

AU - Jun Wang, Qing

AU - Catanzaro, Joseph M.

AU - Friedman, Scott L.

AU - Zong, Wei Xing

AU - Fiel, M. Isabel

AU - Li, Min

AU - Yue, Zhenyu

N1 - Funding Information: This work was supported by National Institutes of Health grants (NIH-R01NS060123) to Z.Y. We thank T. Johansen from The University of Tromsø for mCherry–EGFP–LC3B plasmid; J. Jung from University of Southern California for Flag-UVRAG plasmid; K. Kelley from Mount Sinai mouse genetics core facility for help with embryonic stem cells microinjection; R. Huq and L. O’Rourke from Mount Sinai microscopy core facility; W. Janssen from the Mount Sinai Friedman Brain Institute core facility for help with microscopy; and N. McKnight of the Yue lab for critical reading. We thank T.H. Thin from the immunohistochemistry core of the histology shared resource facility and M. Castillo-Martin from the Department of Pathology at Mount Sinai Hospital for their help with mice tissue immunohistochemistry; and Y. Ge from neurology department, N. Shao from neuroscience department of Icahn School of Medicine at Mount Sinai, Q. Lin and Q. Wang from School of public health, Central South University for their assistance with statistical analysis. We specially thank Ms Lorreta Ho for her generous financial support to the postdoctoral fellowship of J.L.

PY - 2014/5/22

Y1 - 2014/5/22

N2 - The Beclin 1-Vps34 complex, the core component of the class III phosphatidylinositol-3 kinase (PI3K-III), binds Atg14L or UVRAG to control different steps of autophagy. However, the mechanism underlying the control of PI3K-III activity remains elusive. Here we report the identification of NRBF2 as a component in the specific PI3K-III complex and a modulator of PI3K-III activity. Through its microtubule interaction and trafficking (MIT) domain, NRBF2 binds Atg14L directly and enhances Atg14L-linked Vps34 kinase activity and autophagy induction. NRBF2-deficient cells exhibit enhanced vulnerability to endoplasmic reticulum (ER) stress that is reversed by re-introducing exogenous NRBF2. NRBF2-deficient mice develop focal liver necrosis and ductular reaction, accompanied by impaired Atg14L-linked Vps34 activity and autophagy, although the mice show no increased mortality. Our data reveal a key role for NRBF2 in the assembly of the specific Atg14L-Beclin 1-Vps34-Vps15 complex for autophagy induction. Thus, NRBF2 modulates autophagy via regulation of PI3K-III and prevents ER stress-mediated cytotoxicity and liver injury.

AB - The Beclin 1-Vps34 complex, the core component of the class III phosphatidylinositol-3 kinase (PI3K-III), binds Atg14L or UVRAG to control different steps of autophagy. However, the mechanism underlying the control of PI3K-III activity remains elusive. Here we report the identification of NRBF2 as a component in the specific PI3K-III complex and a modulator of PI3K-III activity. Through its microtubule interaction and trafficking (MIT) domain, NRBF2 binds Atg14L directly and enhances Atg14L-linked Vps34 kinase activity and autophagy induction. NRBF2-deficient cells exhibit enhanced vulnerability to endoplasmic reticulum (ER) stress that is reversed by re-introducing exogenous NRBF2. NRBF2-deficient mice develop focal liver necrosis and ductular reaction, accompanied by impaired Atg14L-linked Vps34 activity and autophagy, although the mice show no increased mortality. Our data reveal a key role for NRBF2 in the assembly of the specific Atg14L-Beclin 1-Vps34-Vps15 complex for autophagy induction. Thus, NRBF2 modulates autophagy via regulation of PI3K-III and prevents ER stress-mediated cytotoxicity and liver injury.

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UR - https://www.scopus.com/pages/publications/84901304111#tab=citedBy

U2 - 10.1038/ncomms4920

DO - 10.1038/ncomms4920

M3 - Article

C2 - 24849286

AN - SCOPUS:84901304111

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 3920

ER -

NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

Access to Document

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