The ubiquitin-like protein FAT10 mediates NF-κB activation

Pengfei Gong, Allon Canaan, Bin Wang, Jeremy Leventhal, Alexandra Snyder, Viji Nair, Clemens D. Cohen, Matthias Kretzler, Vivette D'Agati, Sherman Weissman, Michael J. Ross

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55 Scopus citations

Abstract

NF-κB is a central mediator of innate immunity and contributes to the pathogenesis of several renal diseases. FAT10 is a TNF-α-inducible ubiquitin-like protein with a putative role in immune response, but whether FAT10 participates in TNF-α-induced NF-κB activation is unknown. Here, using renal tubular epithelial cells (RTECs) derived from FAT10 -/- and FAT10-/- mice, we observed that FAT10 deficiency abrogated TNF-α-induced NF-κB activation and reduced the induction of NF-κB-regulated genes. Despite normal IkBα degradation and polyubiquitination, FAT10 deficiency impaired TNF-α-induced IkBα degradation and nuclear translocation of p65 in RTECs, suggesting defective proteasomal degradation of polyubiquitinated IkBα. In addition, FAT10 deficiency reduced the expression of the proteasomal subunit low molecular mass polypeptide 2 (LMP2). Transduction of FAT10-/- RTECs with FAT10 restored LMP2 expression, TNF-α-induced IkBα degradation, p65 nuclear translocation, and NF-κB activation. Furthermore, LMP2 transfection restored IkBα degradation in FAT10-/- RTECs. In humans, common types of chronic kidney disease associated with tubulointerstitial upregulation of FAT10. These data suggest that FAT10 mediates NF-κB activation and may promote tubulointerstitial inflammation in chronic kidney diseases.

Original languageEnglish (US)
Pages (from-to)316-326
Number of pages11
JournalJournal of the American Society of Nephrology
Volume21
Issue number2
DOIs
StatePublished - Feb 1 2010
Externally publishedYes

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ASJC Scopus subject areas

  • Nephrology

Cite this

Gong, P., Canaan, A., Wang, B., Leventhal, J., Snyder, A., Nair, V., Cohen, C. D., Kretzler, M., D'Agati, V., Weissman, S., & Ross, M. J. (2010). The ubiquitin-like protein FAT10 mediates NF-κB activation. Journal of the American Society of Nephrology, 21(2), 316-326. https://doi.org/10.1681/ASN.2009050479