title: Stk38 protein kinase preferentially inhibits TLR9-activated inflammatory responses by promoting MEKK2 ubiquitination in macrophages.
abstract: NDR/LATS kinase family is highly conserved from yeast to human. It remains unknown whether the members of this family function in innate immune responses. Here we demonstrate that Stk38 negatively regulates TLR9-mediated immune responses in macrophages. Stk38 constitutively associates with ubiquitin E3 ligase Smurf1, and facilitates Smurf1-mediated MEKK2 ubiquitination and degradation. MEKK2 is required for CpG-induced ERK1/2 activation, TNF-α and IL-6 production but not required for LPS-induced TNF-α and IL-6 production. Accordingly, Stk38 deficiency increases CpG-induced ERK1/2 activation, TNF-α and IL-6 production without significantly affecting LPS-induced TNF-α and IL-6 production. Stk38-deficient mice produce more TNF-α and IL-6, and display increased lethality than control wild-type mice upon E. coli infection. Stk38-deficient mice are also more susceptible to CLP-induced sepsis than control mice. Thus, Stk38 is important in limiting inflammatory cytokine production and necessary for protecting host from inflammatory injury during infection, possibly by negatively regulating TLR9 signalling.
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Wen
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xianwei
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Human Anatomy and Histology and Embryology, Fourth Military Medical University, Xian 710032, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Cheng
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xiongfei
authors.initials: X
authors.lastname: Xu
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Zhenhong
authors.initials: Z
authors.lastname: Guo
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Yu
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Xu
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
authors.affiliation: 1] National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China [2] Cancer Institute, Institute of Translational Medicine, Second Military Medical University, Shanghai 200433, China.
authors.forename: Huazhang
authors.initials: H
authors.lastname: An
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands; D016207:Cytokines / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D004927:Escherichia coli Infections / Q000382:microbiology; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006579:Heterozygote; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D048730:MAP Kinase Kinase Kinase 2 / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D016207:Cytokines; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D048730:MAP Kinase Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases; D048052:Mitogen-Activated Protein Kinase 3; D017346:Protein Serine-Threonine Kinases; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; C492381:Smurf1 protein, mouse; C491614:STK38 protein, human; C482618:MAP3K2 protein, human; C482619:Map3k2 protein, mouse