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Immunity. 2018 Nov 20;49(5):899-914.e6. doi: 10.1016/j.immuni.2018.10.010. Epub 2018 Nov 6.

Hippo Kinases Mst1 and Mst2 Sense and Amplify IL-2R-STAT5 Signaling in Regulatory T Cells to Establish Stable Regulatory Activity.

Author information

1
State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai 200433, China; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, US.
2
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, US.
3
Department of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, US; Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105, US.
4
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, US.
5
Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105, US.
6
State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai 200433, China; Obstetrics & Gynecology Hospital, Fudan University, Shanghai 200433, China. Electronic address: wufan_tao@fudan.edu.cn.
7
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, US. Electronic address: hongbo.chi@stjude.org.

Abstract

Interleukin-2 (IL-2) and downstream transcription factor STAT5 are important for maintaining regulatory T (Treg) cell homeostasis and function. Treg cells can respond to low IL-2 levels, but the mechanisms of STAT5 activation during partial IL-2 deficiency remain uncertain. We identified the serine-threonine kinase Mst1 as a signal-dependent amplifier of IL-2-STAT5 activity in Treg cells. High Mst1 and Mst2 (Mst1-Mst2) activity in Treg cells was crucial to prevent tumor resistance and autoimmunity. Mechanistically, Mst1-Mst2 sensed IL-2 signals to promote the STAT5 activation necessary for Treg cell homeostasis and lineage stability and to maintain the highly suppressive phosphorylated-STAT5+ Treg cell subpopulation. Unbiased quantitative proteomics revealed association of Mst1 with the cytoskeletal DOCK8-LRCHs module. Mst1 deficiency limited Treg cell migration and access to IL-2 and activity of the small GTPase Rac, which mediated downstream STAT5 activation. Collectively, IL-2-STAT5 signaling depends upon Mst1-Mst2 functions to maintain a stable Treg cell pool and immune tolerance.

PMID:
30413360
PMCID:
PMC6249059
[Available on 2019-11-20]
DOI:
10.1016/j.immuni.2018.10.010
[Indexed for MEDLINE]

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