title: Mutant ubiquitin attenuates interleukin-1β- and tumor necrosis factor-α-induced pro-inflammatory signaling in human astrocytic cells.
abstract: A frameshift mutation of ubiquitin called ubiquitin(+1) (UBB(+1)) was found in the aging and Alzheimer's disease brains and thought to be associated with neuronal dysfuction and degeneration. Even though ubiquitylation has been known to regulate vital cellular functions mainly through proteasome-dependent degradation of polyubiquitinated substrates, proteolysis-independent roles of ubiquitylation have emerged as key mechanisms in various signaling cascades. In this study, we have investigated the effect of UBB(+1) on proinflammatory signaling such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in human astrocytes. Treatment with TNF-α and IL-1β induced expression of CCL2 and CXCL8 by human astrocytic cells; while ectopic expression of UBB(+1) significantly abrogated the proinflammatory cytokine-induced expression of chemokines. Ectopic expression of UBB(+1) suppressed TNF-α- and IL-1β-induced activation of NF-κB and JNK signaling pathway. Furthermore, we have demonstrated that polyubiquitylation of TRAFs and subsequent phosphorylation of TAK1 were significantly inhibited by stable expression of UBB(+1). Collectively, these results suggest that UBB(+1) may affect proinflammatory signaling in the central nervous system via inhibitory mechanisms of ubiquitin-dependent signaling in human astrocytes.
authors.affiliation: Cell Signaling and BioImaging Laboratory, Department of Bio and Brain Engineering, KAIST, Daejeon, Korea. ccbioks@kaist.ac.kr
authors.forename: Kyungsun
authors.initials: K
authors.lastname: Choi
authors.forename: Junseong
authors.initials: J
authors.lastname: Park
authors.forename: Jungsul
authors.initials: J
authors.lastname: Lee
authors.forename: Eun Chun
authors.initials: EC
authors.lastname: Han
authors.forename: Chulhee
authors.initials: C
authors.lastname: Choi
mesh_terms: D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002460:Cell Line; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D009154:Mutation; D016328:NF-kappa B / Q000494:pharmacology; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D025801:Ubiquitin / Q000235:genetics* / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018925:Chemokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D016328:NF-kappa B; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; C479419:UBB protein, human; D025801:Ubiquitin