Novel non-canonical role of STAT1 in Natural Killer cell cytotoxicity

Putz, EM; Majoros, A; Gotthardt, D; Prchal-Murphy, M; Zebedin-Brandl, EM; Fux, DA; Schlattl, A; Schreiber, RD; Carotta, S; Muller, M; Gerner, C; DECKER, T; Sexl, V

Author(s): Putz, EM; Majoros, A; Gotthardt, D; Prchal-Murphy, M; Zebedin-Brandl, EM; Fux, DA; Schlattl, A; Schreiber, RD; Carotta, S; Muller, M; Gerner, C; DECKER, T; Sexl, V;
Details: Publication Year 2016,Volume 5,Issue #9,Page e1186314
Journal Title: Oncoimmunology
Publication Type: Journal Article
Abstract: STAT1 is an important regulator of NK cell maturation and cytotoxicity. Although the consequences of Stat1-deficiency have been described in detail the underlying molecular functions of STAT1 in NK cells are only partially understood. Here, we describe a novel non-canonical role of STAT1 that was unmasked in NK cells expressing a Stat1-Y701F mutant. This mutation prevents JAK-dependent phosphorylation, subsequent nuclear translocation and cytokine-induced transcriptional activity as verified by RNA-seq analysis. As expected Stat1-Y701F mice displayed impaired NK cell maturation comparable to Stat1-/- animals. In contrast Stat1-Y701F NK cells exerted a significantly enhanced cytotoxicity in vitro and in vivo compared to Stat1-/- NK cells in the absence of detectable transcriptional activity. We thus investigated the STAT1 interactome using primary NK cells derived from Stat1ind mice that inducibly express a FLAG-tagged STAT1. Mass spectrometry revealed that STAT1 directly binds proteins involved in cell junction formation and proteins associated to membrane or membrane-bound vesicles. In line, immunofluorescence studies uncovered the recruitment of STAT1 to the target-cell interphase during NK cell killing. This led us to propose a novel function for STAT1 at the immunological synapse in NK cells regulating tumor surveillance and cytotoxicity.
Publisher: Taylor & Francis
Research Division(s): Molecular Immunology
PubMed ID: 20160519
Publisher's Version: https://doi.org/10.1080/2162402X.2016.1186314
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2016-10-25 02:58:28

Last Modified: 2016-10-25 04:26:56