Tumor suppressor CYLD regulates acute lung injury in lethal Streptococcus pneumoniae infections.
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.
Lim
Jae Hyang
JH
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Stirling
Brigid
B
Derry
Jonathan
J
Koga
Tomoaki
T
Jono
Hirofumi
H
Woo
Chang-Hoon
CH
Xu
Haodong
H
Bourne
Patricia
P
Ha
Un-Hwan
UH
Ishinaga
Hajime
H
Xu
Haidong
H
Andalibi
Ali
A
Feng
Xin-Hua
XH
Zhu
Hongguang
H
Huang
Yuxian
Y
Zhang
Wenhong
W
Weng
Xinhua
X
Yan
Chen
C
Yin
Zhinan
Z
Briles
David E
DE
Davis
Roger J
RJ
Flavell
Richard A
RA
Li
Jian-Dong
JD
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
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