Dataset Information

Cytokine exocytosis and JAK/STAT activation in the Drosophila ovary requires the vesicle trafficking regulator ?-Snap.

ABSTRACT: How vesicle trafficking components actively contribute to regulation of paracrine signaling is unclear. We genetically uncovered a requirement for ?-soluble NSF attachment protein (?-Snap) in the activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway during Drosophila egg development. ?-Snap, a well-conserved vesicle trafficking regulator, mediates association of N-ethylmaleimide-sensitive factor (NSF) and SNAREs to promote vesicle fusion. Depletion of ?-Snap or the SNARE family member Syntaxin1A in epithelia blocks polar cells maintenance and prevents specification of motile border cells. Blocking apoptosis rescues polar cell maintenance in ?-Snap-depleted egg chambers, indicating that the lack of border cells in mutants is due to impaired signaling. Genetic experiments implicate ?-Snap and NSF in secretion of a STAT-activating cytokine. Live imaging suggests that changes in intracellular Ca2+ are linked to this event. Our data suggest a cell-type specific requirement for particular vesicle trafficking components in regulated exocytosis during development. Given the central role for STAT signaling in immunity, this work may shed light on regulation of cytokine release in humans.

SUBMITTER: Saadin A

PROVIDER: S-EPMC6288073 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Cytokine exocytosis and JAK/STAT activation in the <i>Drosophila</i> ovary requires the vesicle trafficking regulator α-Snap.

Saadin Afsoon A Starz-Gaiano Michelle M

Journal of cell science 20181130 23

How vesicle trafficking components actively contribute to regulation of paracrine signaling is unclear. We genetically uncovered a requirement for α-soluble NSF attachment protein (α-Snap) in the activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway during <i>Drosophila</i> egg development. α-Snap, a well-conserved vesicle trafficking regulator, mediates association of N-ethylmaleimide-sensitive factor (NSF) and SNAREs to promote vesicle fusion. Deple ...[more]

PMID: 30404830

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Project description:BackgroundMutations in lysosomal trafficking regulator (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 patients with CHS and how LYST regulates lytic granule exocytosis is very limited.ObjectiveWe sought to delineate cellular defects associated with LYST mutations responsible for the impaired NK cell function seen in patients with CHS.MethodsWe analyzed NK cells from patients with CHS with missense mutations in the LYST ARM/HEAT (armadillo/huntingtin, elongation factor 3, protein phosphatase 2A, and the yeast kinase TOR1) or BEACH (beige and Chediak-Higashi) domains.ResultsNK cells from patients with CHS 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 immunologic synapse; however, they were unable to properly fuse with the plasma membrane. Mutations in the BEACH domain resulted in formation of normal or slightly enlarged granules that had markedly impaired polarization to the IS but could be exocytosed on reaching the immunologic synapse. Perforin-containing granules in NK cells from patients with CHS did not acquire certain lysosomal markers (lysosome-associated membrane protein 1/2) but were positive for markers of transport vesicles (cation-independent mannose 6-phosphate receptor), late endosomes (Ras-associated binding protein 27a), and, to some extent, early endosomes (early endosome antigen 1), indicating a lack of integrity in the endolysosomal compartments. NK cells from patients with CHS had normal cytokine compartments and cytokine secretion.ConclusionLYST 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 regulation of endolysosomal compartment identity. LYST functions in the regulated exocytosis but not in the constitutive secretion pathway.

Dataset Information

Cytokine exocytosis and JAK/STAT activation in the Drosophila ovary requires the vesicle trafficking regulator ?-Snap.

Publications

Cytokine exocytosis and JAK/STAT activation in the <i>Drosophila</i> ovary requires the vesicle trafficking regulator α-Snap.

Similar Datasets

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