title: Cylindromatosis (CYLD) inhibits Streptococcus pneumonia-induced plasminogen activator inhibitor-1 expression via interacting with TRAF-6.
abstract: Streptococcus pneumoniae (S. p) remains one of the foremost causes of community-acquired pneumonia. Recent studies have shown that S. p lung infection is associated with plasminogen activator inhibitor-1 (PAI-1) expression, which inhibits acute lung injury. Such effects by S. p were negatively regulated by cylindromatosis (CYLD). The current study explored the underlying mechanisms. We showed that S. p-induced PAI-1 expression requires tumor necrosis factor receptor-associated factor 6 (TRAF-6) signaling. Si-RNA-mediated knockdown of TRAF-6 remarkably inhibited S. p-induced PAI-1 expression. Reversely, over-expression of wild type (wt-) TRAF-6 further potentiated PAI-1 expression in S. p-treated cells. We provided evidences to support that CYLD-mediated anti-PAI-1 activity might be through direct regulation of TRAF-6. Our results from co-immunoprecipitation (co-IP) and confocal microscopy assays confirmed a direct association between the CYLD and TRAF-6 in A549 cells. Over-expression of wt-CYLD remarkably inhibited TRAF-6 ubiquitination and subsequent PAI-1 expression. Introducing a mutated CYLD, on the other hand, enhanced TRAF-6 ubiquitination and PAI-1 expression. Together, these results indicate that TRAF-6 mediates S. p-induced PAI-1 expression, and CYLD inhibits PAI-1 expression probably through deubiquitinating TRAF-6. The current study provided molecular insights of CYLD-mediated activities in S. p-induced PAI-1 expression and possible acute lung injury.
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Wenhong
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China. Electronic address: fudanyuxianhuang@163.com.
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Huang
mesh_terms: D002460:Cell Line; D000074749:Deubiquitinating Enzyme CYLD; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011485:Protein Binding; D013296:Streptococcus pneumoniae / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D048029:TNF Receptor-Associated Factor 6; D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD
keywords: Cyindromatosis (CYLD); Deubiquitination; PAI-1; Streptococcus pneumoniae; TRAF-6