Language

English

Publication Date

3-1-2026

Journal

Molecular Biology of the Cell

DOI

10.1091/mbc.E25-08-0368

PMID

41537736

PMCID

PMC12911854

PubMedCentral® Posted Date

6-11-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Rab GTPases are key regulators of endosomal trafficking in eukaryotes. In mammalian cells, Rab4 and Rab7 were shown to localize to distinct compartments, with Rab4 on early endosomes for fast recycling and Rab7 on late endosomes for degradation. Here, we show that in Drosophila, endogenous Rab4 and Rab7 extensively colocalize across tissues and developmental stages. Recruited to the same compartments through mechanisms that do not require the activity of the other, they have opposing effects on endolysosomal size: Rab4 overexpression or Rab7 impairment leads to enlarged endolysosomes, whereas Rab4 loss or constitutively active Rab7 reduces their sizes. Rab4 deficiency suppresses the swelling induced by Rab7 impairment, and conversely, Rab7 activation mitigates the swelling induced by Rab4 overexpression. Genetically, Rab4 loss selectively compromises the viability of rab7-deficient flies but not rab5 or rab11 mutants, supporting a functional overlap between Rab4 and Rab7. Moreover, the levels of endogenous βPS-Integrin, a cargo recycled by Rab4 and degraded via Rab7, are elevated in rab4 mutants and reduced with Rab4 overexpression. Lastly, Rab4 and Rab7 show notable colocalization in mammalian cells and mouse brains, and live imaging reveals dynamic β1-integrin trafficking between Rab4- and Rab7-positive endosomes. Together, these data support that in addition to recycling, Rab4 plays a role in degradation by directing its cargos such as β1-integrin into Rab7-mediated late endolysosomal pathway.

Keywords

Animals, Lysosomes, Endosomes, rab GTP-Binding Proteins, rab7 GTP-Binding Proteins, Drosophila Proteins, rab4 GTP-Binding Proteins, Protein Transport, Drosophila melanogaster, rab5 GTP-Binding Proteins, Proteolysis, Drosophila, Rab4, Rab7, endolysosomal homeostasis, cargo degradation, Drosophila model

Published Open-Access

yes

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