title: Human biliverdin reductase suppresses Goodpasture antigen-binding protein (GPBP) kinase activity: the reductase regulates tumor necrosis factor-alpha-NF-kappaB-dependent GPBP expression.
abstract: The Ser/Thr/Tyr kinase activity of human biliverdin reductase (hBVR) and the expression of Goodpasture antigen-binding protein (GPBP), a nonconventional Ser/Thr kinase for the type IV collagen of basement membrane, are regulated by tumor necrosis factor (TNF-alpha). The pro-inflammatory cytokine stimulates kinase activity of hBVR and activates NF-kappaB, a transcriptional regulator of GPBP mRNA. Increased GPBP activity is associated with several autoimmune conditions, including Goodpasture syndrome. Here we show that in HEK293A cells hBVR binds to GPBP and down-regulates its TNF-alpha-stimulated kinase activity; this was not due to a decrease in GPBP expression. Findings with small interfering RNA to hBVR and to the p65 regulatory subunit of NF-kappaB show the hBVR role in the initial stimulation of GPBP expression by TNF-alpha-activated NF-kappaB; hBVR was not a factor in mediating GPBP mRNA stability. The interacting domain was mapped to the (281)CX(10)C motif in the C-terminal 24 residues of hBVR. A 7-residue peptide, KKRILHC(281), corresponding to the core of the consensus D(delta)-Box motif in the interacting domain, was as effective as the intact 296-residue hBVR polypeptide in inhibiting GPBP kinase activity. GPBP neither regulated hBVR expression nor TNF-alpha dependent NF-kappaB expression. Collectively, our data reveal that hBVR is a regulator of the TNF-alpha-GPBP-collagen type IV signaling cascade and uncover a novel biological interaction that may be of relevance in autoimmune pathogenesis.
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
authors.forename: Tihomir
authors.initials: T
authors.lastname: Miralem
authors.forename: Peter E M
authors.initials: PE
authors.lastname: Gibbs
authors.forename: Fernando
authors.initials: F
authors.lastname: Revert
authors.forename: Juan
authors.initials: J
authors.lastname: Saus
authors.forename: Mahin D
authors.initials: MD
authors.lastname: Maines
mesh_terms: D020816:Amino Acid Motifs; D019867:Anti-Glomerular Basement Membrane Disease / Q000378:metabolism / Q000628:therapy; D002460:Cell Line; D024141:Collagen Type IV / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D017434:Protein Structure, Tertiary; D020871:RNA Stability; D034741:RNA, Small Interfering; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D024141:Collagen Type IV; C498143:RELA protein, human; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D011494:Protein Kinases; C119090:CERT1 protein, human; D017346:Protein Serine-Threonine Kinases