Kiely_2020_Deubiquitinase.pdf (2.59 MB)
The deubiquitinase USP7 uses a distinct ubiquitin-like domain to deubiquitinate NF-kB subunits
journal contributionposted on 2023-01-17, 10:18 authored by Izaskun Mitxitorena, Domenico Somma, Jennifer P. Mitchell, Matti Lepistö, Christian Tyrchan, Emma L. Smith, PATRICK KIELYPATRICK KIELY, Helen Walden, Karen Keeshan, Ruaidhrí J. Carmody
The transcription factor NF-kB is a master regulator of the innate immune response and plays a central role in inflammatory diseases by mediating the expression of pro-inflammatory cytokines.Ubiquitination-triggered proteasomal degradation of DNA-bound NF-kB strongly limits the expression of its target genes. Conversely, USP7 (deubiquitinase ubiquitin-specific peptidase7) opposes the activities of E3ligases,stabilizes DNAbound NF-kB, and thereby promotes NF-kB–mediated transcription. Using gene expression and synthetic peptide arrays on membrane support and overlay analyses, we found here that inhibiting USP7 increases NF-kB ubiquitination and degradation, prevents Toll-like receptor–induced pro-inflammatory cytokine expression, and represents an effective strategy for controlling inflammation. However, the broad regulatory roles of USP7 in cell death pathways, chromatin, and DNA damage responses limit the use of catalytic inhibitors of USP7 as anti inflammatory agents. To this end,we identified nNF-kB–binding site in USP7, ubiquitin-like domain 2, that selectively mediates interactions of USP7 with NF-kB subunits but is dispensable for interactions with other proteins. Moreover, we found that the amino acids 757LDEL760 in USP7 critically contribute to the interaction with the p65 subunit of NF-ŒB. Our findings support the notion that USP7 activity could be potentially targeted in a substrate-selective manner through the development of noncatalytic inhibitors of this deubiquitinase to abrogate NF-kB activity.
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PublicationJournal of Biological Chemistry;295(33), pp. 11754–11763
PublisherThe American Society for Biochemistry and Molecular Biology
Other Funding informationMedical Research Council, Biological Sciences Research Council
Also affiliated with
- Bernal Institute
- Health Research Institute (HRI)
Department or School
- School of Medicine