title: Tumor suppressor CYLD regulates acute lung injury in lethal Streptococcus pneumoniae infections.
abstract: Streptococcus pneumoniae (S. pneumoniae) causes high early mortality in pneumococcal pneumonia, which is characterized by acute lung injury (ALI). The molecular mechanisms underlying ALI and the high early mortality remain unknown. Despite recent studies that identify deubiquitinating enzyme cylindromatosis (CYLD) as a key regulator for T cell development, tumor cell proliferation, and NF-kappaB transcription factor signaling, its role in regulating bacteria-induced lethality, however, is unknown. Here, we showed that CYLD deficiency protected mice from S. pneumoniae pneumolysin (PLY)-induced ALI and lethality. CYLD was highly induced by PLY, and it inhibited MKK3-p38 kinase-dependent expression of plasminogen activator inhibitor-1 (PAI-1) in lung, thereby potentiating ALI and mortality. Thus, CYLD is detrimental for host survival, thereby indicating a mechanism underlying the high early mortality of pneumococcal pneumonia.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Jae Hyang
authors.initials: JH
authors.lastname: Lim
authors.forename: Brigid
authors.initials: B
authors.lastname: Stirling
authors.forename: Jonathan
authors.initials: J
authors.lastname: Derry
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Koga
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Woo
authors.forename: Haodong
authors.initials: H
authors.lastname: Xu
authors.forename: Patricia
authors.initials: P
authors.lastname: Bourne
authors.forename: Un-Hwan
authors.initials: UH
authors.lastname: Ha
authors.forename: Hajime
authors.initials: H
authors.lastname: Ishinaga
authors.forename: Haidong
authors.initials: H
authors.lastname: Xu
authors.forename: Ali
authors.initials: A
authors.lastname: Andalibi
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.forename: Hongguang
authors.initials: H
authors.lastname: Zhu
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Huang
authors.forename: Wenhong
authors.initials: W
authors.lastname: Zhang
authors.forename: Xinhua
authors.initials: X
authors.lastname: Weng
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Yin
authors.forename: David E
authors.initials: DE
authors.lastname: Briles
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000502:physiology*; D000074749:Deubiquitinating Enzyme CYLD; D008168:Lung / Q000201:enzymology / Q000473:pathology*; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D011008:Pneumococcal Infections / Q000201:enzymology / Q000473:pathology; D011018:Pneumonia, Pneumococcal / Q000201:enzymology / Q000401:mortality* / Q000473:pathology*; D058258:Serpin E2; D015843:Serpins / Q000235:genetics / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000472:pathogenicity; D013301:Streptolysins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; D013301:Streptolysins; D025521:Tumor Suppressor Proteins; C032290:plY protein, Streptococcus pneumoniae; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases