A third distinct tumor necrosis factor receptor of orthopoxviruses

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 95; no. 7; pp. 3786 - 3791
• Main Authors: Loparev, V.N. (National Center for Infectious Diseases, Atlanta, GA.), Parsons, J.M, Knight, J.C, Panus, J.F, Ray, C.A, Buller, R.M.L, Pickup, D.J, Esposito, J.J
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 31-03-1998; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Amino Acid Sequence; AMINO ACID SEQUENCES; Amino acids; ANIMAL VIRUSES; BINDING; BINDING SITES; Biological Sciences; Cell culture techniques; CHEMICAL COMPOSITION; COWPOX VIRUS; Cultured cells; CYTOKINES; CYTOTOXICITY; DNA; ECTROMELIA VIRUS; GENBANK/U87234; GENBANK/U87235; GENBANK/U87578; GENBANK/U87579; GENBANK/U87580; GENBANK/U87581; GENBANK/U87582; GENBANK/U87583; GENBANK/U93910; GENES; Genomes; GLYCOPROTEINS; Glycoproteins - analysis; Glycoproteins - genetics; Humans; IMMUNOLOGICAL DISEASES; Immunology; Ligands; LYMPHOTOXIN-ALPHA; MICROBIAL PROTEINS; MOLECULAR SEQUENCE DATA; NUCLEOTIDE SEQUENCE; ORTHOPOXVIRUS; Orthopoxvirus - genetics; Orthopoxvirus - metabolism; Poxviridae; Proteins; Receptors, Tumor Necrosis Factor - analysis; Receptors, Tumor Necrosis Factor - genetics; Sequence Alignment; STRUCTURAL GENES; TOXICITY; Tumor Necrosis Factor-alpha - metabolism; VIRAL IMMUNOSUPPRESSION; Viral Proteins - analysis; Viral Proteins - genetics; Virology; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.7.3786

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 (LT alpha) and blocked their in vitro cytolytic activity. Secreted viral CrmD bound TNF and LT alpha 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