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Endosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36.

ABSTRACT: Ligand-induced epidermal growth factor receptor (EGFR) endocytosis followed by endosomal EGFR signaling and lysosomal degradation plays important roles in controlling multiple biological processes. ADP-ribosylation factor (Arf)-like protein 4 A (Arl4A) functions at the plasma membrane to mediate cytoskeletal remodeling and cell migration, whereas its localization at endosomal compartments remains functionally unknown. Here, we report that Arl4A attenuates EGFR degradation by binding to the endosomal sorting complex required for transport (ESCRT)-II component VPS36. Arl4A plays a role in prolonging the duration of EGFR ubiquitinylation and deterring endocytosed EGFR transport from endosomes to lysosomes under EGF stimulation. Mechanistically, the Arl4A-VPS36 direct interaction stabilizes VPS36 and ESCRT-III association, affecting subsequent recruitment of deubiquitinating-enzyme USP8 by CHMP2A. Impaired Arl4A-VPS36 interaction enhances EGFR degradation and clearance of EGFR ubiquitinylation. Together, we discover that Arl4A negatively regulates EGFR degradation by binding to VPS36 and attenuating ESCRT-mediated late endosomal EGFR sorting.

SUBMITTER: Lin SJ

PROVIDER: S-EPMC10687025 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Endosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36.

Lin Shin-Jin SJ Lin Ming-Chieh MC Liu Tsai-Jung TJ Tsai Yueh-Tso YT Tsai Ming-Ting MT Lee Fang-Jen S FS

Nature communications 20231129 1

Ligand-induced epidermal growth factor receptor (EGFR) endocytosis followed by endosomal EGFR signaling and lysosomal degradation plays important roles in controlling multiple biological processes. ADP-ribosylation factor (Arf)-like protein 4 A (Arl4A) functions at the plasma membrane to mediate cytoskeletal remodeling and cell migration, whereas its localization at endosomal compartments remains functionally unknown. Here, we report that Arl4A attenuates EGFR degradation by binding to the endos ...[more]

PMID: 38030597

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Project description:BackgroundVps25p is the product of yeast gene VPS25 and is found in an endosomal sorting complex required for transport (ESCRT)-II, along with Vps22p and Vps36p. This complex is essential for sorting of ubiquitinated biosynthetic and endosomal cargoes into endosomes.ResultsWe found that VPS25 is a highly conserved and widely expressed eukaryotic gene, with single orthologs in chromalveolate, excavate, amoebozoan, plant, fungal and metazoan species. Two paralogs were found in Trichomonas vaginalis. An ortholog was strikingly absent from the Encephalitozoon cuniculi genome. Intron positions were analyzed in VPS25 from 36 species. We found evidence for five ancestral VPS25 introns, intron loss, and single instances of intron gain (a Paramecium species) and intron slippage (Theileria species). Processed pseudogenes were identified in four mammalian genomes, with a notable absence in the mouse genome. Two retropseudogenes were found in the chimpanzee genome, one more recently inserted, and one evolving from a common primate ancestor. The amino acid sequences of 119 Vps25 orthologs are aligned, compared with the known secondary structure of yeast Vps25p, and used to carry out phylogenetic analysis. Residues in two amino-terminal PPXY motifs (motif I and II), involved in dimerization of Vps25p and interaction with Vps22p and Vps36p, were closely, but not absolutely conserved. Specifically, motif I was absent in Vps25 homologs of chromalveolates, euglenozoa, and diplomonads. A highly conserved carboxy-terminal lysine was identified, which suggests Vps25 is ubiquitinated. Arginine-83 of yeast Vps25p involved in Vps22p interaction was highly, but not absolutely, conserved. Human tissue expression analysis showed universal expression.ConclusionWe have identified 119 orthologs of yeast Vps25p. Expression of mammalian VPS25 in a wide range of tissues, and the presence in a broad range of eukaryotic species, indicates a basic role in eukaryotic cell function. Intron splice site positions were highly conserved across all major eukaryotic species, suggesting an ancestral origin. Amino acid sequence analysis showed the consensus for the amino-terminal proline-rich motifs is P- [WP]-X-[YF] for motif I (when present) and P-P-[FYL]-[FY] for motif II, and that Vps25 may be ubiquitinated.

Dataset Information

Endosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36.

Publications

Endosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36.

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