A Commander-independent function of COMMD3 in endosomal trafficking
Endosomal recycling is a branch of intracellular membrane trafficking that retrieves endocytosed cargo proteins from early and late endosomes to prevent their degradation in lysosomes. A key player in endosomal recycling is the Commander complex, a 16-subunit protein assembly that cooperates with ot...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2025-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/105264 |
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| author | Galen T Squiers Chun Wan James Gorder Harrison Puscher Jingshi Shen |
| author_facet | Galen T Squiers Chun Wan James Gorder Harrison Puscher Jingshi Shen |
| author_sort | Galen T Squiers |
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| description | Endosomal recycling is a branch of intracellular membrane trafficking that retrieves endocytosed cargo proteins from early and late endosomes to prevent their degradation in lysosomes. A key player in endosomal recycling is the Commander complex, a 16-subunit protein assembly that cooperates with other endosomal factors to recruit cargo proteins and facilitate the formation of tubulo-vesicular carriers. While the crucial role of Commander in endosomal recycling is well established, its molecular mechanism remains poorly understood. Here, we genetically dissected the Commander complex using unbiased genetic screens and comparative targeted mutations. Unexpectedly, our findings revealed a Commander-independent function for COMMD3, a subunit of the Commander complex, in endosomal recycling. COMMD3 regulates a subset of cargo proteins independently of the other Commander subunits. The Commander-independent function of COMMD3 is mediated by its N-terminal domain (NTD), which binds and stabilizes ADP-ribosylation factor 1 (ARF1), a small GTPase regulating endosomal recycling. Mutations disrupting the COMMD3-ARF1 interaction diminish ARF1 expression and impair COMMD3-dependent cargo recycling. These data provide direct evidence that Commander subunits can function outside the holo-complex and raise the intriguing possibility that components of other membrane trafficking complexes may also possess functions beyond their respective complexes. |
| format | Article |
| id | doaj-art-ded8a1614f6842eabecc573358567337 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-ded8a1614f6842eabecc5733585673372025-08-21T14:23:57ZengeLife Sciences Publications LtdeLife2050-084X2025-08-011410.7554/eLife.105264A Commander-independent function of COMMD3 in endosomal traffickingGalen T Squiers0Chun Wan1James Gorder2Harrison Puscher3Jingshi Shen4https://orcid.org/0000-0001-9595-1148Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, United StatesDepartment of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, United StatesDepartment of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, United StatesDepartment of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, United StatesDepartment of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, United StatesEndosomal recycling is a branch of intracellular membrane trafficking that retrieves endocytosed cargo proteins from early and late endosomes to prevent their degradation in lysosomes. A key player in endosomal recycling is the Commander complex, a 16-subunit protein assembly that cooperates with other endosomal factors to recruit cargo proteins and facilitate the formation of tubulo-vesicular carriers. While the crucial role of Commander in endosomal recycling is well established, its molecular mechanism remains poorly understood. Here, we genetically dissected the Commander complex using unbiased genetic screens and comparative targeted mutations. Unexpectedly, our findings revealed a Commander-independent function for COMMD3, a subunit of the Commander complex, in endosomal recycling. COMMD3 regulates a subset of cargo proteins independently of the other Commander subunits. The Commander-independent function of COMMD3 is mediated by its N-terminal domain (NTD), which binds and stabilizes ADP-ribosylation factor 1 (ARF1), a small GTPase regulating endosomal recycling. Mutations disrupting the COMMD3-ARF1 interaction diminish ARF1 expression and impair COMMD3-dependent cargo recycling. These data provide direct evidence that Commander subunits can function outside the holo-complex and raise the intriguing possibility that components of other membrane trafficking complexes may also possess functions beyond their respective complexes.https://elifesciences.org/articles/105264endosomal recyclingmembrane traffickingvesicle buddingCommanderCOMMD3 |
| spellingShingle | Galen T Squiers Chun Wan James Gorder Harrison Puscher Jingshi Shen A Commander-independent function of COMMD3 in endosomal trafficking eLife endosomal recycling membrane trafficking vesicle budding Commander COMMD3 |
| title | A Commander-independent function of COMMD3 in endosomal trafficking |
| title_full | A Commander-independent function of COMMD3 in endosomal trafficking |
| title_fullStr | A Commander-independent function of COMMD3 in endosomal trafficking |
| title_full_unstemmed | A Commander-independent function of COMMD3 in endosomal trafficking |
| title_short | A Commander-independent function of COMMD3 in endosomal trafficking |
| title_sort | commander independent function of commd3 in endosomal trafficking |
| topic | endosomal recycling membrane trafficking vesicle budding Commander COMMD3 |
| url | https://elifesciences.org/articles/105264 |
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