The lysosomal trafficking regulator "LYST": an 80-year traffic jam

Abstract

Lysosomes and lysosome related organelles (LROs) are dynamic organelles at the intersection of various pathways involved in maintaining cellular hemostasis and regulating cellular functions. Vesicle trafficking of lysosomes and LROs are critical to maintain their functions. The lysosomal trafficking regulator (LYST) is an elusive protein important for the regulation of membrane dynamics and intracellular trafficking of lysosomes and LROs. Mutations to the LYST gene result in Chédiak-Higashi syndrome, an autosomal recessive immunodeficiency characterized by defective granule exocytosis, cytotoxicity, etc. Despite eight decades passing since its initial discovery, a comprehensive understanding of LYST's function in cellular biology remains unresolved. Accumulating evidence suggests that dysregulation of LYST function also manifests in other disease states. Here, we review the available literature to consolidate available scientific endeavors in relation to LYST and discuss its relevance for immunomodulatory therapies, regenerative medicine and cancer applications.

Keywords: Chédiak-Higashi syndrome; LYST; beige; cancer; immunotherapy; lysosomes; vesicle traffic; wound healing.

Figure 1

A Summary of Cell Specific LYST-Deficient Phenotypes. Acronyms (from left to right): Natural killer (NK) cells, Macrophages (MΦ), Platelets (PLT), cells of the nervous system, Mast cells (MC), B cells, Cytotoxic T cells, Polymorphonuclear leukocytes (PMN), Fibroblasts (FIB). The size of the cell reflects the amount of literature available. Created with BioRender.com.

Figure 2

LYST Mutation and Correlation with Clinical Phenotypes. (A) The color gradient indicates the relative frequencies of specific disease phenotypes associated with each domain (e.g. Immune Defects account for 22.22% of cases with BEACH domain mutations). The 19 major phenotypes are categorized into eight groups and presented alphabetically, including: Abnormal Pigmentation (1. silver gray hair, 2. cutaneous albinism/partial albinism, 3. ocular albinism), Blood/Coagulation Disorders (4. coagulopathy/platelet dysfunctions, 5. isolated cytopenia, 6. pancytopenia), 7. Enlarged/Abnormal Granules, Immune Defects (8. fever/rash/lymphadenopathy, 9. oral infection/periodontitis, 10. defective/absent NK cell activity, 11. CMV/EBV seropositive, 12. respiratory infection, 13. recurrent infections), Muscular Dysfunction (14. motor dysfunction/myopathy/hypotonia), Neurological Disorders (15. GDD/intellectual disability/dementia, 16. neuropathy, 17. atrophic MRI brain), 18. Ocular Symptoms (i.e. myopia), and 19. Organomegaly (i.e. hepato/splenomegaly). (B) The mutation loci and their associated phenotypes are indicated on a schematic representation of the LYST protein spanning from exon 1 to exon 53, with a note indicating putative domains. Created with BioRender.com.