Natural killer (NK) cell–mediated killing involves the membrane fusion of preformed lytic granules. While the roles of actin and microtubules are well accepted during this process, the function of septins, another cytoskeletal component that associates with actin and microtubules, has not been investigated. Here we show that genetic depletion or pharmacologic stabilization of the septin cytoskeleton significantly inhibited NK cell cytotoxicity. Although the stabilization of septin filaments impaired conjugate formation, depletion of septin proteins had no impact on conjugate formation, lytic granule convergence, or MTOC polarization to the cytotoxic synapse (CS). Interestingly, septins copurify and accumulate near the polarized lytic granules at the CS, where they regulate lytic granule release. Mechanistically, we find that septin 7 interacts with the SNARE protein syntaxin 11 and facilitates its interaction with syntaxin binding protein 2 to promote lytic granule fusion. Altogether, our data identify a critical role for septins in regulating the release of lytic granule contents during NK cell–mediated killing.
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2 November 2020
Article|
August 24 2020
The septin cytoskeleton regulates natural killer cell lytic granule release
Prasad V. Phatarpekar
,
Prasad V. Phatarpekar
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN
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Brittany L. Overlee
,
Brittany L. Overlee
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN
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Alexander Leehan
,
Alexander Leehan
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN
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Katelynn M. Wilton
,
Katelynn M. Wilton
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN
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Hyoungjun Ham
,
Hyoungjun Ham
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN
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Daniel D. Billadeau
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN
Correspondence to Daniel D. Billadeau: billadeau.daniel@mayo.edu
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Prasad V. Phatarpekar
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN
Brittany L. Overlee
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN
Alexander Leehan
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN
Katelynn M. Wilton
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN
Hyoungjun Ham
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN
Daniel D. Billadeau
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN
Correspondence to Daniel D. Billadeau: billadeau.daniel@mayo.edu
Received:
February 25 2020
Revision Received:
June 26 2020
Accepted:
July 28 2020
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding:
Mayo Clinic
(P30 CA015083)
Mayo Foundation for Medical Education and Research
(NO AWARD)
National Institute of Allergy and Infectious Diseases
(R01-AI120949)
© 2020 Phatarpekar et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2020) 219 (11): e202002145.
Article history
Received:
February 25 2020
Revision Received:
June 26 2020
Accepted:
July 28 2020
Citation
Prasad V. Phatarpekar, Brittany L. Overlee, Alexander Leehan, Katelynn M. Wilton, Hyoungjun Ham, Daniel D. Billadeau; The septin cytoskeleton regulates natural killer cell lytic granule release. J Cell Biol 2 November 2020; 219 (11): e202002145. doi: https://doi.org/10.1083/jcb.202002145
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