Lamtor5, also known as HBXIP, is a subunit of the Ragulator. It mediates the activation of mechanistic target of rapamycin complex 1 (mTORC1) in response to amino acids. Lamtor5 is involved in multiple cellular processes such as lysosome function regulation, immune response, and metabolism, making it biologically significant. Genetic models, like KO/CKO mouse models, are valuable for studying its functions [1,2].

In a study, mice with myeloid Lamtor5 ablation developed SLE-like manifestations. In Lamtor5-deficient macrophages and PBMCs of SLE patients, there were impaired lysosomal function, aberrant mTORC1 activation, a blunted autolysosomal pathway, and undesirable inflammatory responses. Lamtor5 was shown to physically associate with ATP6V1A, promoting V0/V1 holoenzyme assembly for lysosome acidification, and its binding to v-ATPase affected lysosomal tethering of Rag GTPase and mTORC1 activation, suggesting its role in immune homeostasis [1]. Also, Lamtor5-deficient mice had sustained inflammation and increased mortality during endotoxic shock due to delayed TLR4 degradation as Lamtor5 normally facilitates TLR4 autophagic degradation by preventing mTORC1 activation and derepressing TFEB [2].

In conclusion, Lamtor5 is crucial for immune homeostasis by integrating v-ATPase activity, lysosome function, and mTOR pathway. Its deficiency in mouse models reveals its role in autoimmune diseases like SLE and in controlling inflammation during endotoxic shock, providing potential therapeutic targets for these disease areas.

References:

1. Zhang, Wei, Sha, Zhou, Tang, Yunzhe, Wang, Dandan, Shi, Liyun. 2024. Defective Lamtor5 Leads to Autoimmunity by Deregulating v-ATPase and Lysosomal Acidification. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2400446. doi:10.1002/advs.202400446. https://pubmed.ncbi.nlm.nih.gov/38639386/

2. Zhang, Wei, Zhuang, Ningtong, Liu, Xiaoyi, Xu, Dakang, Shi, Liyun. 2019. The metabolic regulator Lamtor5 suppresses inflammatory signaling via regulating mTOR-mediated TLR4 degradation. In Cellular & molecular immunology, 17, 1063-1076. doi:10.1038/s41423-019-0281-6. https://pubmed.ncbi.nlm.nih.gov/31467416/