Biogenesis of lysosome-related organelles complex-2 is an evolutionarily ancient proto-coatomer complex.

Autor:	Thomason PA; Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. Electronic address: p.thomason@crukscotlandinstitute.ac.uk., Corbyn R; Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK., Lilla S; Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK., Sumpton D; Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK., Gilbey T; Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK., Insall RH; School of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK; Division of Cell & Developmental Biology, University College London, London WC1E 6BT, UK. Electronic address: r.insall@ucl.ac.uk.
Jazyk:	angličtina
Zdroj:	Current biology : CB [Curr Biol] 2024 Aug 05; Vol. 34 (15), pp. 3564-3581.e6. Date of Electronic Publication: 2024 Jul 25.
DOI:	10.1016/j.cub.2024.06.081
Abstrakt:	Hermansky-Pudlak syndrome (HPS) is an inherited disorder of intracellular vesicle trafficking affecting the function of lysosome-related organelles (LROs). At least 11 genes underlie the disease, encoding four protein complexes, of which biogenesis of lysosome-related organelles complex-2 (BLOC-2) is the last whose molecular action is unknown. We find that the unicellular eukaryote Dictyostelium unexpectedly contains a complete BLOC-2, comprising orthologs of the mammalian subunits HPS3, -5, and -6, and a fourth subunit, an ortholog of the Drosophila LRO-biogenesis gene, Claret. Lysosomes from Dictyostelium BLOC-2 mutants fail to mature, similar to LROs from HPS patients, but for all endolysosomes rather than a specialized subset. They also strongly resemble lysosomes from WASH mutants. Dictyostelium BLOC-2 localizes to the same compartments as WASH, and in BLOC-2 mutants, WASH is inefficiently recruited, accounting for their impaired lysosomal maturation. BLOC-2 is recruited to endolysosomes via its HPS3 subunit. Structural modeling suggests that all four subunits are proto-coatomer proteins, with important implications for BLOC-2's molecular function. The discovery of Dictyostelium BLOC-2 permits identification of orthologs throughout eukaryotes. BLOC-2 and lysosome-related organelles, therefore, pre-date the evolution of Metazoa and have broader and more conserved functions than previously thought. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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