ALG-2 activates the MVB sorting function of ALIX through relieving its intramolecular interaction

Sheng Sun; Xi Zhou; Joe Corvera; Gary E. Gallick; Sue Hwa Lin; Jian Kuang

doi:10.1038/celldisc.2015.18

ALG-2 activates the MVB sorting function of ALIX through relieving its intramolecular interaction

Sheng Sun, Xi Zhou, Joe Corvera, Gary E. Gallick, Sue Hwa Lin, Jian Kuang

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

24 Scopus citations

Abstract

The modular adaptor protein ALIX is critically involved in endosomal sorting complexes required for transport (ESCRT)-mediated multivesicular body (MVB) sorting of activated epidermal growth factor receptor (EGFR); however, ALIX contains a default intramolecular interaction that renders ALIX unable to perform this ESCRT function. The ALIX partner protein ALG-2 is a calcium-binding protein that belongs to the calmodulin superfamily. Prompted by a defined biological function of calmodulin, we determined the role of ALG-2 in regulating ALIX involvement in MVB sorting of activated EGFR. Our results show that calcium-dependent ALG-2 interaction with ALIX completely relieves the intramolecular interaction of ALIX and promotes CHMP4-dependent ALIX association with the membrane. EGFR activation induces increased ALG-2 interaction with ALIX, and this increased interaction is responsible for increased ALIX association with the membrane. Functionally, inhibition of ALIX activation by ALG-2 inhibits MVB sorting of activated EGFR as effectively as inhibition of ALIX interaction with CHMP4 does; however, inhibition of ALIX activation by ALG-2 does not affect cytokinetic abscission or equine infectious anemia virus (EIAV) budding. These findings indicate that calcium-dependent ALG-2 interaction with ALIX is specifically responsible for generating functional ALIX that supports MVB sorting of ubiquitinated membrane receptors.

Original language	English (US)
Article number	15018
Journal	Cell Discovery
Volume	1
DOIs	https://doi.org/10.1038/celldisc.2015.18
State	Published - Jul 21 2015

Keywords

ALG-2
ALIX
CHMP4
EGFR
MVB sorting

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Genetics
Cell Biology

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10.1038/celldisc.2015.18

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@article{8af4a6a7f86048f6b48932209c8cf40f,

title = "ALG-2 activates the MVB sorting function of ALIX through relieving its intramolecular interaction",

abstract = "The modular adaptor protein ALIX is critically involved in endosomal sorting complexes required for transport (ESCRT)-mediated multivesicular body (MVB) sorting of activated epidermal growth factor receptor (EGFR); however, ALIX contains a default intramolecular interaction that renders ALIX unable to perform this ESCRT function. The ALIX partner protein ALG-2 is a calcium-binding protein that belongs to the calmodulin superfamily. Prompted by a defined biological function of calmodulin, we determined the role of ALG-2 in regulating ALIX involvement in MVB sorting of activated EGFR. Our results show that calcium-dependent ALG-2 interaction with ALIX completely relieves the intramolecular interaction of ALIX and promotes CHMP4-dependent ALIX association with the membrane. EGFR activation induces increased ALG-2 interaction with ALIX, and this increased interaction is responsible for increased ALIX association with the membrane. Functionally, inhibition of ALIX activation by ALG-2 inhibits MVB sorting of activated EGFR as effectively as inhibition of ALIX interaction with CHMP4 does; however, inhibition of ALIX activation by ALG-2 does not affect cytokinetic abscission or equine infectious anemia virus (EIAV) budding. These findings indicate that calcium-dependent ALG-2 interaction with ALIX is specifically responsible for generating functional ALIX that supports MVB sorting of ubiquitinated membrane receptors.",

keywords = "ALG-2, ALIX, CHMP4, EGFR, MVB sorting",

author = "Sheng Sun and Xi Zhou and Joe Corvera and Gallick, {Gary E.} and Lin, {Sue Hwa} and Jian Kuang",

note = "Funding Information: This work was supported by NIH/NCI grant 1 RO1 CA93941, NHARP grant 01878, and IRG grants awarded to JK. We thank Drs Changmin Chen (Boston, MA, USA), Masatoshi Maki (Nagoya, Japan), Robert Mealey (Pullman, WA, USA), Jean Gruenberg (Geneva, Switzerland), Olsen (Chapel Hill, NC, USA) and Wesley I Sundquist (Salt Lake City, Utah, USA) for generously providing reagents. DNA sequencing was performed by the DNA Analysis Facility of UT MD Anderson Cancer Center, which is supported by the NCI Grant CA-16672.",

year = "2015",

month = jul,

day = "21",

doi = "10.1038/celldisc.2015.18",

language = "English (US)",

volume = "1",

journal = "Cell Discovery",

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T1 - ALG-2 activates the MVB sorting function of ALIX through relieving its intramolecular interaction

AU - Sun, Sheng

AU - Zhou, Xi

AU - Corvera, Joe

AU - Gallick, Gary E.

AU - Lin, Sue Hwa

AU - Kuang, Jian

N1 - Funding Information: This work was supported by NIH/NCI grant 1 RO1 CA93941, NHARP grant 01878, and IRG grants awarded to JK. We thank Drs Changmin Chen (Boston, MA, USA), Masatoshi Maki (Nagoya, Japan), Robert Mealey (Pullman, WA, USA), Jean Gruenberg (Geneva, Switzerland), Olsen (Chapel Hill, NC, USA) and Wesley I Sundquist (Salt Lake City, Utah, USA) for generously providing reagents. DNA sequencing was performed by the DNA Analysis Facility of UT MD Anderson Cancer Center, which is supported by the NCI Grant CA-16672.

PY - 2015/7/21

Y1 - 2015/7/21

N2 - The modular adaptor protein ALIX is critically involved in endosomal sorting complexes required for transport (ESCRT)-mediated multivesicular body (MVB) sorting of activated epidermal growth factor receptor (EGFR); however, ALIX contains a default intramolecular interaction that renders ALIX unable to perform this ESCRT function. The ALIX partner protein ALG-2 is a calcium-binding protein that belongs to the calmodulin superfamily. Prompted by a defined biological function of calmodulin, we determined the role of ALG-2 in regulating ALIX involvement in MVB sorting of activated EGFR. Our results show that calcium-dependent ALG-2 interaction with ALIX completely relieves the intramolecular interaction of ALIX and promotes CHMP4-dependent ALIX association with the membrane. EGFR activation induces increased ALG-2 interaction with ALIX, and this increased interaction is responsible for increased ALIX association with the membrane. Functionally, inhibition of ALIX activation by ALG-2 inhibits MVB sorting of activated EGFR as effectively as inhibition of ALIX interaction with CHMP4 does; however, inhibition of ALIX activation by ALG-2 does not affect cytokinetic abscission or equine infectious anemia virus (EIAV) budding. These findings indicate that calcium-dependent ALG-2 interaction with ALIX is specifically responsible for generating functional ALIX that supports MVB sorting of ubiquitinated membrane receptors.

AB - The modular adaptor protein ALIX is critically involved in endosomal sorting complexes required for transport (ESCRT)-mediated multivesicular body (MVB) sorting of activated epidermal growth factor receptor (EGFR); however, ALIX contains a default intramolecular interaction that renders ALIX unable to perform this ESCRT function. The ALIX partner protein ALG-2 is a calcium-binding protein that belongs to the calmodulin superfamily. Prompted by a defined biological function of calmodulin, we determined the role of ALG-2 in regulating ALIX involvement in MVB sorting of activated EGFR. Our results show that calcium-dependent ALG-2 interaction with ALIX completely relieves the intramolecular interaction of ALIX and promotes CHMP4-dependent ALIX association with the membrane. EGFR activation induces increased ALG-2 interaction with ALIX, and this increased interaction is responsible for increased ALIX association with the membrane. Functionally, inhibition of ALIX activation by ALG-2 inhibits MVB sorting of activated EGFR as effectively as inhibition of ALIX interaction with CHMP4 does; however, inhibition of ALIX activation by ALG-2 does not affect cytokinetic abscission or equine infectious anemia virus (EIAV) budding. These findings indicate that calcium-dependent ALG-2 interaction with ALIX is specifically responsible for generating functional ALIX that supports MVB sorting of ubiquitinated membrane receptors.

KW - ALG-2

KW - ALIX

KW - CHMP4

KW - EGFR

KW - MVB sorting

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DO - 10.1038/celldisc.2015.18

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C2 - 27462417

AN - SCOPUS:84984858024

SN - 2056-5968

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JO - Cell Discovery

JF - Cell Discovery

M1 - 15018

ER -

ALG-2 activates the MVB sorting function of ALIX through relieving its intramolecular interaction

Abstract

Keywords

ASJC Scopus subject areas

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