title: A network of interactions enables CCM3 and STK24 to coordinate UNC13D-driven vesicle exocytosis in neutrophils.
abstract: Neutrophil degranulation plays an important role in acute innate immune responses and is tightly regulated because the granule contents can cause tissue damage. However, this regulation remains poorly understood. Here, we identify the complex of STK24 and CCM3 as being an important regulator of neutrophil degranulation. Lack of either STK24 or CCM3 increases the release of a specific granule pool without affecting other neutrophil functions. STK24 appears to suppress exocytosis by interacting and competing with UNC13D C2B domain for lipid binding, whereas CCM3 has dual roles in exocytosis regulation. Although CCM3 stabilizes STK24, it counteracts STK24-mediated inhibition of exocytosis by recruiting STK24 away from the C2B domain through its Ca(2+)-sensitive interaction with UNC13D C2A domain. This STK24/CCM3-regulated exocytosis plays an important role in the protection of kidneys from ischemia-reperfusion injury. Together, these findings reveal a function of the STK24 and CCM3 complex in the regulation of ligand-stimulated exocytosis.
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA; Department of Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA; Department of Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA; Department of Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Niu
authors.affiliation: Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yingke
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA; Department of Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Gao
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
authors.forename: Weijun
authors.initials: W
authors.lastname: Pan
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.affiliation: Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Toomre
authors.affiliation: Department of Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address: wang.min@yale.edu.
authors.forename: Wang
authors.initials: W
authors.lastname: Min
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA; Department of Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address: dan.wu@yale.edu.
authors.forename: Dianqing
authors.initials: D
authors.lastname: Wu
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology; D005089:Exocytosis; D007113:Immunity, Innate; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015427:Reperfusion Injury / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; C559318:PDCD10 protein, mouse; C520225:Unc13d protein, mouse; C585515:Stk24 protein, mouse; D000099317:Hippo Kinases; C530661:Stk25 protein, mouse