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

IF 7.4 1区 生物学 Q1 CELL BIOLOGY
Journal of Cell Biology Pub Date : 2024-10-07 Epub Date: 2024-07-30 DOI:10.1083/jcb.202402016
Jinglin Li, Qiuyuan Yin, Nan Xuan, Qiwen Gan, Chaolian Liu, Qian Zhang, Mei Yang, Chonglin Yang
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引用次数: 0

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.

LYSMD蛋白可促进Rab32家族GTP酶的活化,从而促进溶酶体相关细胞器的生物生成。
溶酶体相关细胞器(LROs)是特化的溶酶体,在机体平衡中具有细胞类型特异性的作用。溶酶体相关细胞器的失调会导致许多人类疾病,但它们的生物发生机制尚未完全明了。在这里,我们发现一组 LYSMD 蛋白是进化保守的 LROs 调节因子。在秀丽隐杆线虫(Caenorhabditis elegans)中,LMD-2(一种含LysM结构域的蛋白)的突变会降低肠道特异性LRO(肠道颗粒)上的Rab32 GTP酶同源物GLO-1的水平,导致其异常增大和生物发生缺陷。LMD-2 与 GLO-1 的鸟嘌呤核苷酸交换因子(GEF)亚基 GLO-3 相互作用,从而促进 GLO-1 的活化。哺乳动物中 LMD-2 的同源物 LYSMD1 和 LYSMD2 可以在功能上替代 elegans 中的 LMD-2。在哺乳动物中,LYSMD1/2 与 Rab32/38 的 GEF BLOC-3 的 HPS1 亚基发生物理作用,从而促进 Rab32 的活化。LYSMD1 和 LYSMD2 失活会降低 Rab32 的活化,导致小鼠黑色素瘤细胞中黑色素体增大和黑色素生成减少。这些发现提供了有关 LRO 生物发生和功能的重要机理见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Cell Biology
Journal of Cell Biology 生物-细胞生物学
CiteScore
12.60
自引率
2.60%
发文量
213
审稿时长
1 months
期刊介绍: The Journal of Cell Biology (JCB) is a comprehensive journal dedicated to publishing original discoveries across all realms of cell biology. We invite papers presenting novel cellular or molecular advancements in various domains of basic cell biology, along with applied cell biology research in diverse systems such as immunology, neurobiology, metabolism, virology, developmental biology, and plant biology. We enthusiastically welcome submissions showcasing significant findings of interest to cell biologists, irrespective of the experimental approach.
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