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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-35304

Gong, Pengfei; 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-kappaB activation. Journal of the American Society of Nephrology (JASN), 21(2):316-326.

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Abstract

NF-kappaB is a central mediator of innate immunity and contributes to the pathogenesis of several renal diseases. FAT10 is a TNF-alpha-inducible ubiquitin-like protein with a putative role in immune response, but whether FAT10 participates in TNF-alpha-induced NF-kappaB activation is unknown. Here, using renal tubular epithelial cells (RTECs) derived from FAT10(-/-) and FAT10(+/+) mice, we observed that FAT10 deficiency abrogated TNF-alpha-induced NF-kappaB activation and reduced the induction of NF-kappaB-regulated genes. Despite normal IkBalpha degradation and polyubiquitination, FAT10 deficiency impaired TNF-alpha-induced IkBalpha degradation and nuclear translocation of p65 in RTECs, suggesting defective proteasomal degradation of polyubiquitinated IkBalpha. 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-alpha-induced IkBalpha degradation, p65 nuclear translocation, and NF-kappaB activation. Furthermore, LMP2 transfection restored IkBalpha 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-kappaB activation and may promote tubulointerstitial inflammation in chronic kidney diseases.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Nephrology
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:February 2010
Deposited On:03 Aug 2010 11:55
Last Modified:04 Dec 2013 14:20
Publisher:American Society of Nephrology
ISSN:1046-6673
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1681/ASN.2009050479
PubMed ID:19959714

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