PLoS ONE (Jan 2013)

Mutant ubiquitin attenuates interleukin-1β- and tumor necrosis factor-α-induced pro-inflammatory signaling in human astrocytic cells.

  • Kyungsun Choi,
  • Junseong Park,
  • Jungsul Lee,
  • Eun Chun Han,
  • Chulhee Choi

DOI
https://doi.org/10.1371/journal.pone.0067891
Journal volume & issue
Vol. 8, no. 7
p. e67891

Abstract

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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.