Cited by 37Cellular transport and secretionUbiquitin and proteasome pathwaysAutophagy in Disease and Therapy

Unravelling the pivotal role of Alix in MVB sorting and silencing of the activated EGFR

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Sun, Sheng, Zhou, Xi, Zhang, Wei, Gallick, Gary E., Kuang, Jian·2015·Biochemical Journal

Abstract

Endosomal sorting complex required for transport (ESCRT)-III-mediated membrane invagination and scission are a critical step in multivesicular body (MVB) sorting of ubiquitinated membrane receptors, and generally thought to be required for degradation of these receptors in lysosomes. The adaptor protein Alix is critically involved in multiple ESCRT-III-mediated, membrane-remodelling processes in mammalian cells. However, Alix knockdown does not inhibit degradation of the activated epidermal growth factor receptor (EGFR) in mammalian cell lines, leading to a widely held notion that Alix is not critically involved in MVB sorting of ubiquitinated membrane receptors in mammalian cells. In the present study, we demonstrate that, despite its non-essential role in degradation of the activated EGFR, Alix plays a critical role in its MVB sorting and silencing Epidermal growth factor (EGF) stimulation of mammalian cell lines induces Alix's interaction with the ubiquitinated EGFR via the Alix V domain, and increases Alix's association with membrane-bound charged multivesicular body protein 4 (CHMP4) via the Alix Bro1 domain. Under both continuous and pulse-chase EGF stimulation conditions, inhibition of Alix's interaction with membrane-bound CHMP4, inhibition of Alix dimerization through the V domain or Alix knockdown dramatically inhibits MVB sorting of the activated EGFR and promotes sustained activation of extracellular-signal regulated kinase (ERK)1/2. Under the continuous EGF stimulation conditions, these cell treatments also retard degradation of the activated EGFR. These findings indicate that Alix is critically involved in MVB sorting of ubiquitinated membrane receptors in mammalian cells.

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  • Loss of Alix protein involved in ILV biogenesis in MVBs resulted in alteration of membrane budding, a decrease in the number of ELV released, and modifications of ELV-MT composition.

    “In their study, loss of Alix protein involved in ILV biogenesis in MVBs (Sun et al., 2015) resulted in alteration of membrane budding, a decrease in the number of ELV released and a modifications of ELV-MT composition”

    From Skeletal Muscle-Released Extracellular Vesicles: State of the Art (2019) · cites this paper as Sun et al., 2015

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Authors
Sun, S., Zhou, X., Zhang, W., Gallick, G. E., & Kuang, J.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • Beijing Normal University (CN)
Corresponding author
  • Sun, Sheng
  • Zhou, Xi
  • Kuang, Jian
Venue
Biochemical Journal
Published
2015-03-06
Volume
466
Issue
3
Pages
475-487
ISSN
  • 0264-6021 (ISSN-L)
  • 1470-8728
OpenAlex
W2043952539
Cited by
37
References
54
Citations by year
2026: 2 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 3 · 2016: 9 · 2015: 1
FWCI
2.16
Type
journal article
Language
en
Open access
Locations
  • Biochemical Journal (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (CA-16672, 1 RO1 CA93941, R01CA093941, P30CA016672)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
Alix, ESCRT-III, epidermal growth factor receptor, receptor degradation, Bro1 domain, V domain, ERK1/2 activation, receptor internalization, lysosomal degradation
MeSH terms
Calcium-Binding Proteins, Epidermal Growth Factor, Humans, Cell Cycle Proteins, Ubiquitination, Endosomal Sorting Complexes Required for Transport, Multivesicular Bodies, HEK293 Cells, ErbB Receptors

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