LYSMD proteins promote activation of Rab32-family GTPases for lysosome-related organelle biogenesis

Author:

Li Jinglin1ORCID,Yin Qiuyuan1ORCID,Xuan Nan1ORCID,Gan Qiwen1ORCID,Liu Chaolian1ORCID,Zhang Qian1ORCID,Yang Mei1ORCID,Yang Chonglin12ORCID

Affiliation:

1. Center for Life Sciences, School of Life Sciences, Yunnan University 1 , Kunming, China

2. Southwest United Graduate School, Yunnan University 2 , Kunming, China

Abstract

Lysosome-related organelles (LROs) are specialized lysosomes with cell type–specific roles in organismal homeostasis. Dysregulation of LROs leads to many human disorders, but the mechanisms underlying their biogenesis are not fully understood. Here, we identify a group of LYSMD proteins as evolutionarily conserved regulators of LROs. In Caenorhabditis elegans, mutations of LMD-2, a LysM domain–containing protein, reduce the levels of the Rab32 GTPase ortholog GLO-1 on intestine-specific LROs, the gut granules, leading to their abnormal enlargement and defective biogenesis. LMD-2 interacts with GLO-3, a subunit of GLO-1 guanine nucleotide exchange factor (GEF), thereby promoting GLO-1 activation. Mammalian homologs of LMD-2, LYSMD1, and LYSMD2 can functionally replace LMD-2 in C. elegans. In mammals, LYSMD1/2 physically interact with the HPS1 subunit of BLOC-3, the GEF of Rab32/38, thus promoting Rab32 activation. Inactivation of both LYSMD1 and LYSMD2 reduces Rab32 activation, causing melanosome enlargement and decreased melanin production in mouse melanoma cells. These findings provide important mechanistic insights into LRO biogenesis and functions.

Funder

National Science Foundation of China

National Basic Research Program of China

Yunnan Province Science and Technology Department

Program of Yunnan Province Leading Talents in Science and Technology

Publisher

Rockefeller University Press

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