title: A third distinct tumor necrosis factor receptor of orthopoxviruses.
abstract: Cowpox virus Brighton red strain (CPV) contains a gene, crmD, which encodes a 320-aa tumor necrosis factor receptor (TNFR) of 44% and 22% identity, respectively, to the CPV TNFR-like proteins, cytokine response modifiers (crm) CrmB and CrmC. The crmD gene was interrupted in three other cowpox strains examined and absent in various other orthopoxviruses; however, four strains of ectromelia virus (ECT) examined contained an intact crmD (97% identity to CPV crmD) and lacked cognates of crmB and crmC. The protein, CrmD, contains a transport signal; a 151-aa cysteine-rich region with 21 cysteines that align with human TNFRII ligand-binding region cysteines; and C-terminal region sequences that are highly diverged from cellular TNFR C-terminal region sequences involved in signal transduction. Bacterial maltose-binding proteins containing the CPV or ECT CrmD cysteine-rich region bound TNF and lymphotoxin-alpha (LTalpha) and blocked their in vitro cytolytic activity. Secreted viral CrmD bound TNF and LTalpha and was detectable after the early stage of replication, using nonreducing conditions, as 60- to 70-kDa predominant and 90- to 250-kDa minor disulfide-linked complexes that were able to be reduced to a 46-kDa form and deglycosylated to a 38-kDa protein. Cells infected with CPV produced extremely low amounts of CrmD compared with ECT. Possessing up to three TNFRs, including CrmD, which is secreted as disulfide-linked complexes in varied amounts by CPV and ECT, likely enhances the dynamics of the immune modulating mechanisms of orthopoxviruses.
authors.affiliation: Poxvirus Section, Viral Exanthems and Herpesvirus Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: V N
authors.initials: VN
authors.lastname: Loparev
authors.forename: J M
authors.initials: JM
authors.lastname: Parsons
authors.forename: J C
authors.initials: JC
authors.lastname: Knight
authors.forename: J F
authors.initials: JF
authors.lastname: Panus
authors.forename: C A
authors.initials: CA
authors.lastname: Ray
authors.forename: R M
authors.initials: RM
authors.lastname: Buller
authors.forename: D J
authors.initials: DJ
authors.lastname: Pickup
authors.forename: J J
authors.initials: JJ
authors.lastname: Esposito
mesh_terms: D000595:Amino Acid Sequence; D006023:Glycoproteins / Q000032:analysis* / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D018155:Orthopoxvirus / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis* / Q000235:genetics; D016415:Sequence Alignment; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014764:Viral Proteins / Q000032:analysis / Q000235:genetics
chemical_list: D006023:Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins