<scp>LYST</scp> Affects Lysosome Size and Quantity, but not Trafficking or Degradation Through Autophagy or Endocytosis

Holland, Petter; Torgersen, Maria Lyngaas; Sandvig, Kirsten; Simonsen, Anne

doi:10.1111/tra.12227

Cited by 38 publications

(35 citation statements)

References 47 publications

(58 reference statements)

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“…LysoTracker, an acidotropic probe, stained both normal and CHS NK cells to the same extent (data not shown), indicating that pH of the granules in CHS NK cells is not affected, which agrees with reports showing that the acidification of large granules in CHS cells is not changed. 56, 57 We did not observe any difference in granzyme B activity between normal and CHS NK cells, and others have shown that processing and enzymatic activity of several lysosomal enzymes is not affected in CHS cells, 23, 57 implying that despite their mixed identity and enlarged size the granules are functional in CHS.…”

Section: Discussionmentioning

confidence: 42%

Chediak-Higashi syndrome: Lysosomal trafficking regulator domains regulate exocytosis of lytic granules but not cytokine secretion by natural killer cells

Gil-Krzewska

Wood

Murakami

et al. 2016

Journal of Allergy and Clinical Immunology

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Background Mutations in LYST cause Chediak-Higashi syndrome (CHS), a rare immunodeficiency with impaired cytotoxic lymphocyte function, mainly that of natural killer (NK) cells. Our understanding of NK cell function deficiency in CHS, and how LYST regulates lytic granule exocytosis is very limited. Objective We sought to delineate cellular defects, associated with LYST mutations, responsible for the impaired NK cell function in CHS. Methods We analyzed NK cells from CHS patients with missense mutations in the LYST ARM/HEAT or BEACH domains. Results CHS NK cells displayed severely reduced cytotoxicity. Mutations in the ARM/HEAT domain led to a reduced number of perforin-containing granules, which were significantly increased in size, but able to polarize to the immunological synapse (IS); however, they were unable to properly fuse with the plasma membrane. Mutations in the BEACH domain resulted in the formation of normal or slightly enlarged granules that had markedly impaired polarization to the immunological synapse, but could be exocytosed upon reaching the IS. Perforin-containing granules in CHS NK cells did not acquire certain lysosomal markers (LAMP1/2), but were positive for markers of transport vesicles (CI-MPR), late endosomes (Rab27a), and to some extent, early endosomes (EEA-1), indicating a lack of integrity in the endo-lysosomal compartments. CHS NK cells had normal cytokine compartments and cytokine secretion. Conclusion LYST is involved in regulation of multiple aspects of NK cell lytic activity ranging from governance of lytic granule size to control of their polarization and exocytosis, as well as the regulation of endo-lysosomal compartment identity. LYST functions in the regulated exocytosis, but not in the constitutive secretion pathway.

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Section: Discussionmentioning

confidence: 42%

Chediak-Higashi syndrome: Lysosomal trafficking regulator domains regulate exocytosis of lytic granules but not cytokine secretion by natural killer cells

Gil-Krzewska

Wood

Murakami

et al. 2016

Journal of Allergy and Clinical Immunology

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“…This discrepancy may reflect a difference between unstimulated lymphocytes freshly isolated from blood and CTL clones cultured in cytokines over several weeks. In non-immune cell lines, siRNA to LYST induces enlarged lysosomes but did not affect the size of early endosomes or result in localization of early endosome proteins to enlarged lysosomes (52). The presence of LYST during organelle biogenesis prior to the siRNA treatment may preserve early endosome morphology, or there may be a cell type-specific defect in immune cells or cells with specialized secretory lysosomes.…”

Section: Discussionmentioning

confidence: 99%

Differences in Granule Morphology yet Equally Impaired Exocytosis among Cytotoxic T Cells and NK Cells from Chediak–Higashi Syndrome Patients

et al. 2017

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Chediak–Higashi syndrome (CHS) is caused by autosomal recessive mutations in LYST, resulting in enlarged lysosomal compartments in multiple cell types. CHS patients display oculocutaneous albinism and may develop life-threatening hemophagocytic lymphohistiocytosis (HLH). While NK cell-mediated cytotoxicity has been reported to be uniformly defective, variable defects in T cell-mediated cytotoxicity has been observed. The latter has been linked to the degree of HLH susceptibility. Since the discrepancies in NK cell- and T cell-mediated cellular cytotoxicity might result from differences in regulation of cytotoxic granule release, we here evaluated perforin-containing secretory lysosome size and number in freshly isolated lymphocytes from CHS patients and furthermore compared their exocytic capacities. Whereas NK cells from CHS patients generally contained a single, gigantic perforin-containing granule, cytotoxic T cells predominantly contained several smaller granules. Nonetheless, in a cohort of 21 CHS patients, cytotoxic T cell and NK cell granule exocytosis were similarly impaired upon activating receptor stimulation. Mechanistically, polarization of cytotoxic granules was defective in cytotoxic lymphocytes from CHS patients, with EEA1, a marker of early endosomes, mislocalizing to lysosomal structures. The results leads to the conclusion that lysosome enlargement corresponds to loss of distinct organelle identity in the endocytic pathway, which on a subcellular level more adversely affects NK cells than T cells. Hence, vesicular size or numbers do not per se dictate the impairment of lysosomal exocytosis in the two cell types studied.

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“…The defective gene, LYST or CHS1, encodes a ~4000 amino acid protein with several identifiable protein domains including BEACH, pleckstrin homology, WD40 repeats, perilipin‐like, lectin‐like and HEAT/Armadillo‐like repeats . LYST is thought to either promote fission of endolysosomal organelles or prevent their fusion, as the giant organelles in CTLs, NK cells and other cell types from CHS patients or its beige mouse model contain markers of both late endosomes/lysosomes and early endosomes . However, the mechanism by which LYST does so is not yet clear.…”

Section: Additional Disorders Of Lro Biogenesis Secretion and Motilitymentioning

confidence: 99%

The road to lysosome‐related organelles: Insights from Hermansky‐Pudlak syndrome and other rare diseases

Bowman

Bi‐Karchin

et al. 2019

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Lysosome-related organelles (LROs) comprise a diverse group of cell type-specific, membrane-bound subcellular organelles that derive at least in part from the endolysosomal system but that have unique contents, morphologies and functions to support specific physiological roles. They include: melanosomes that provide pigment to our eyes and skin; alpha and dense granules in platelets, and lytic granules in cytotoxic T cells and natural killer cells, which release effectors to regulate hemostasis and immunity; and distinct classes of lamellar bodies in lung epithelial cells and keratinocytes that support lung plasticity and skin lubrication. The formation, maturation and/or secretion of subsets of LROs are dysfunctional or entirely absent in a number of hereditary syndromic disorders, including in particular the Hermansky-Pudlak syndromes. This review provides a comprehensive overview of LROs in humans and model organisms and presents our current understanding of how the products of genes that are defective in heritable diseases impact their formation, motility and ultimate secretion.

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LYST Affects Lysosome Size and Quantity, but not Trafficking or Degradation Through Autophagy or Endocytosis

Cited by 38 publications

References 47 publications

Chediak-Higashi syndrome: Lysosomal trafficking regulator domains regulate exocytosis of lytic granules but not cytokine secretion by natural killer cells

Chediak-Higashi syndrome: Lysosomal trafficking regulator domains regulate exocytosis of lytic granules but not cytokine secretion by natural killer cells

Differences in Granule Morphology yet Equally Impaired Exocytosis among Cytotoxic T Cells and NK Cells from Chediak–Higashi Syndrome Patients

The road to lysosome‐related organelles: Insights from Hermansky‐Pudlak syndrome and other rare diseases

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