PMID- 36707427 OWN - NLM STAT- MEDLINE DCOM- 20230131 LR - 20240516 IS - 1420-9071 (Electronic) IS - 1420-682X (Print) IS - 1420-682X (Linking) VI - 80 IP - 2 DP - 2023 Jan 28 TI - LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size. PG - 53 LID - 10.1007/s00018-023-04695-x [doi] LID - 53 AB - Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by biallelic mutations in the lysosomal trafficking regulator (LYST) gene. Even though enlarged lysosomes and/or lysosome-related organelles (LROs) are the typical cellular hallmarks of CHS, they have not been investigated in human neuronal models. Moreover, how and why the loss of LYST function causes a lysosome phenotype in cells has not been elucidated. We report that the LYST-deficient human neuronal model exhibits lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes. These results have also been recapitulated in neurons differentiated from CHS patients' induced pluripotent stem cells (iPSCs), validating our model system. We propose that LYST ensures the correct fission/scission of the autolysosome tubules during autophagic lysosome reformation (ALR), a crucial process to restore the number of free lysosomes after autophagy. We further demonstrate that LYST is recruited to the lysosome membrane, likely to facilitate the fission of autolysosome tubules. Together, our results highlight the key role of LYST in maintaining lysosomal homeostasis following autophagy and suggest that ALR dysregulation is likely associated with the neurodegenerative CHS phenotype. CI - (c) 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. FAU - Serra-Vinardell, Jenny AU - Serra-Vinardell J AUID- ORCID: 0000-0002-2851-6776 AD - Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA. jennyserravinardell@gmail.com. FAU - Sandler, Maxwell B AU - Sandler MB AD - Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA. FAU - De Pace, Raffaella AU - De Pace R AUID- ORCID: 0000-0002-8179-6869 AD - Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA. FAU - Manzella-Lapeira, Javier AU - Manzella-Lapeira J AD - Twinbrook Imaging Facility, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20892, USA. FAU - Cougnoux, Antony AU - Cougnoux A AUID- ORCID: 0000-0001-9407-7540 AD - Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA. FAU - Keyvanfar, Keyvan AU - Keyvanfar K AD - National Heart, Lung, and Blood Institute, Flow Cytometry Facility, National Institutes of Health, Bethesda, MD, 20892, USA. FAU - Introne, Wendy J AU - Introne WJ AD - Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA. FAU - Brzostowski, Joseph A AU - Brzostowski JA AUID- ORCID: 0000-0003-0257-3905 AD - Twinbrook Imaging Facility, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20892, USA. FAU - Ward, Michael E AU - Ward ME AUID- ORCID: 0000-0002-5296-8051 AD - National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, 20892, USA. FAU - Gahl, William A AU - Gahl WA AUID- ORCID: 0000-0002-2494-6752 AD - Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA. AD - Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Common Fund, Office of the Director, NIH, Bethesda, MD, 20892, USA. FAU - Sharma, Prashant AU - Sharma P AUID- ORCID: 0000-0002-1165-980X AD - Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Common Fund, Office of the Director, NIH, Bethesda, MD, 20892, USA. sharmap@nih.gov. FAU - Malicdan, May Christine V AU - Malicdan MCV AD - Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA. AD - Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Common Fund, Office of the Director, NIH, Bethesda, MD, 20892, USA. LA - eng PT - Journal Article DEP - 20230128 PL - Switzerland TA - Cell Mol Life Sci JT - Cellular and molecular life sciences : CMLS JID - 9705402 RN - 0 (Vesicular Transport Proteins) RN - 0 (LYST protein, human) SB - IM EIN - Cell Mol Life Sci. 2023 Mar 4;80(3):81. PMID: 36869920 MH - Humans MH - *Vesicular Transport Proteins/genetics MH - Lysosomes/physiology MH - Organelles MH - Autophagy/physiology MH - *Chediak-Higashi Syndrome/genetics MH - Neurons PMC - PMC11072721 OTO - NOTNLM OT - Autolysosome tubule OT - Autolysosomes OT - Chediak-Higashi syndrome OT - Lysosome fission OT - Protolysosomes OT - iPSC COIS- The authors have non-financial interests to disclose. EDAT- 2023/01/28 06:00 MHDA- 2023/02/01 06:00 PMCR- 2023/01/28 CRDT- 2023/01/27 23:13 PHST- 2022/07/22 00:00 [received] PHST- 2023/01/08 00:00 [accepted] PHST- 2022/12/11 00:00 [revised] PHST- 2023/01/27 23:13 [entrez] PHST- 2023/01/28 06:00 [pubmed] PHST- 2023/02/01 06:00 [medline] PHST- 2023/01/28 00:00 [pmc-release] AID - 10.1007/s00018-023-04695-x [pii] AID - 4695 [pii] AID - 10.1007/s00018-023-04695-x [doi] PST - epublish SO - Cell Mol Life Sci. 2023 Jan 28;80(2):53. doi: 10.1007/s00018-023-04695-x.