PMID- 35239671
OWN - NLM
STAT- MEDLINE
DCOM- 20220310
LR  - 20221006
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 17
IP  - 3
DP  - 2022
TI  - Deficiency in Lyst function leads to accumulation of secreted proteases and 
      reduced retinal adhesion.
PG  - e0254469
LID - 10.1371/journal.pone.0254469 [doi]
LID - e0254469
AB  - Chediak-Higashi syndrome, caused by mutations in the Lysosome Trafficking 
      Regulator (Lyst) gene, is a recessive hypopigmentation disorder characterized by 
      albinism, neuropathies, neurodegeneration, and defective immune responses, with 
      enlargement of lysosomes and lysosome-related organelles. Although recent studies 
      have suggested that Lyst mutations impair the regulation of sizes of lysosome and 
      lysosome-related organelle, the underlying pathogenic mechanism of 
      Chediak-Higashi syndrome is still unclear. Here we show striking evidence that 
      deficiency in LYST protein function leads to accumulation of photoreceptor outer 
      segment phagosomes in retinal pigment epithelial cells, and reduces adhesion 
      between photoreceptor outer segment and retinal pigment epithelial cells in a 
      mouse model of Chediak-Higashi syndrome. In addition, we observe elevated levels 
      of cathepsins, matrix metallopeptidase (MMP) 3 and oxidative stress markers in 
      the retinal pigment epithelium of Lyst mutants. Previous reports showed that 
      impaired degradation of photoreceptor outer segment phagosomes causes elevated 
      oxidative stress, which could consequently lead to increases of cysteine 
      cathepsins and MMPs in the extracellular matrix. Taken together, we conclude that 
      the loss of LYST function causes accumulation of phagosomes in the retinal 
      pigment epithelium and elevation of several extracellular matrix-remodeling 
      proteases through oxidative stress, which may, in turn, reduce retinal adhesion. 
      Our work reveals previously unreported pathogenic events in the retinal pigment 
      epithelium caused by Lyst deficiency. The same pathogenic events may be conserved 
      in other professional phagocytic cells, such as macrophages in the immune system, 
      contributing to overall Chediak-Higashi syndrome pathology.
FAU - Ji, Xiaojie
AU  - Ji X
AD  - The Jackson Laboratory, Bar Harbor, ME, United States of America.
AD  - Graduate School of Biomedical Science and Engineering, University of Maine, 
      Orono, ME, United States of America.
FAU - Zhao, Lihong
AU  - Zhao L
AD  - The Jackson Laboratory, Bar Harbor, ME, United States of America.
FAU - Umapathy, Ankita
AU  - Umapathy A
AD  - Department of Ophthalmology and Stein Eye Institute, University of California, 
      Los Angeles, CA, United States of America.
FAU - Fitzmaurice, Bernard
AU  - Fitzmaurice B
AD  - The Jackson Laboratory, Bar Harbor, ME, United States of America.
FAU - Wang, Jieping
AU  - Wang J
AD  - The Jackson Laboratory, Bar Harbor, ME, United States of America.
FAU - Williams, David S
AU  - Williams DS
AD  - Department of Ophthalmology and Stein Eye Institute, University of California, 
      Los Angeles, CA, United States of America.
AD  - Department of Neurobiology, David Geffen School of Medicine, UCLA, Los Angeles, 
      CA, United States of America.
AD  - Molecular Biology Institute, UCLA, Los Angeles, CA, United States of America.
AD  - Brain Research Institute, UCLA, Los Angeles, CA, United States of America.
FAU - Chang, Bo
AU  - Chang B
AD  - The Jackson Laboratory, Bar Harbor, ME, United States of America.
FAU - Naggert, Jurgen K
AU  - Naggert JK
AD  - The Jackson Laboratory, Bar Harbor, ME, United States of America.
FAU - Nishina, Patsy M
AU  - Nishina PM
AUID- ORCID: 0000-0003-1640-5945
AD  - The Jackson Laboratory, Bar Harbor, ME, United States of America.
LA  - eng
GR  - R01 EY011996/EY/NEI NIH HHS/United States
GR  - U54 AG054345/AG/NIA NIH HHS/United States
GR  - P30 CA034196/CA/NCI NIH HHS/United States
GR  - P30 EY000331/EY/NEI NIH HHS/United States
GR  - R01 EY019943/EY/NEI NIH HHS/United States
GR  - R01 EY027442/EY/NEI NIH HHS/United States
GR  - R01 EY027860/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20220303
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - EC 3.4.- (Peptide Hydrolases)
SB  - IM
MH  - *Peptide Hydrolases
PMC - PMC8893605
COIS- The authors declare no conflict of interest.
EDAT- 2022/03/04 06:00
MHDA- 2022/03/11 06:00
PMCR- 2022/03/03
CRDT- 2022/03/03 17:14
PHST- 2021/06/16 00:00 [received]
PHST- 2022/02/18 00:00 [accepted]
PHST- 2022/03/03 17:14 [entrez]
PHST- 2022/03/04 06:00 [pubmed]
PHST- 2022/03/11 06:00 [medline]
PHST- 2022/03/03 00:00 [pmc-release]
AID - PONE-D-21-19819 [pii]
AID - 10.1371/journal.pone.0254469 [doi]
PST - epublish
SO  - PLoS One. 2022 Mar 3;17(3):e0254469. doi: 10.1371/journal.pone.0254469. 
      eCollection 2022.