Lyst-KO Mouse

LYST, the lysosomal trafficking regulator, is crucial for the regulation of membrane dynamics and intracellular trafficking of lysosomes and lysosome-related organelles (LROs). Lysosomes and LROs are dynamic organelles involved in maintaining cellular hemostasis and regulating cellular functions, and LYST-mediated vesicle trafficking is essential for their proper function [1].

Mutations in the LYST gene cause Chédiak-Higashi syndrome, an autosomal recessive immunodeficiency. In LYST-deficient human neuronal models and neurons differentiated from CHS patients' induced pluripotent stem cells, there is lysosome depletion with hyperelongated tubules extruding from enlarged autolysosomes, suggesting LYST is needed for correct fission/scission of autolysosome tubules during autophagic lysosome reformation to maintain lysosomal homeostasis [2]. In a mouse model of Chediak-Higashi syndrome, LYST deficiency leads to accumulation of photoreceptor outer segment phagosomes in retinal pigment epithelial cells, reduced retinal adhesion, and elevated levels of certain proteases and oxidative stress markers [3]. The yeast LYST homolog Bph1, when absent, causes lipidated Atg8 to accumulate on endosomes, reduced selective autophagy flux, and defective endocytosis, indicating a role in maintaining endosomal functioning [4].

In conclusion, LYST is key for maintaining lysosomal and endosomal functions. Studies using models with LYST deficiency, such as human neuronal models, patient-derived iPSCs, and mouse models, have revealed its importance in autophagic lysosome reformation, retinal function, and endosomal processes. These findings contribute to understanding the pathogenesis of Chédiak-Higashi syndrome and potentially other related diseases [1,2,3,4].

References:

1. Turner, Mackenzie E, Che, Jingru, Mirhaidari, Gabriel J M, Best, Cameron A, Barker, Jenny C. 2024. The lysosomal trafficking regulator "LYST": an 80-year traffic jam. In Frontiers in immunology, 15, 1404846. doi:10.3389/fimmu.2024.1404846. https://pubmed.ncbi.nlm.nih.gov/38774881/

2. Serra-Vinardell, Jenny, Sandler, Maxwell B, De Pace, Raffaella, Sharma, Prashant, Malicdan, May Christine V. 2023. LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size. In Cellular and molecular life sciences : CMLS, 80, 53. doi:10.1007/s00018-023-04695-x. https://pubmed.ncbi.nlm.nih.gov/36707427/

3. Ji, Xiaojie, Zhao, Lihong, Umapathy, Ankita, Naggert, Jürgen K, Nishina, Patsy M. 2022. Deficiency in Lyst function leads to accumulation of secreted proteases and reduced retinal adhesion. In PloS one, 17, e0254469. doi:10.1371/journal.pone.0254469. https://pubmed.ncbi.nlm.nih.gov/35239671/

4. Vargas Duarte, Prado, Hardenberg, Ralph, Mari, Muriel, González Montoro, Ayelén, Ungermann, Christian. 2022. The yeast LYST homolog Bph1 is a Rab5 effector and prevents Atg8 lipidation at endosomes. In Journal of cell science, 135, . doi:10.1242/jcs.259421. https://pubmed.ncbi.nlm.nih.gov/35343566/