Table.

Structure and Function of Deubiquitinases in NF-κB Signaling and Associated Disorders.

Ubiquitin-Editing Enzymes	Structure	Targeted Substrates	Function	Related Human Diseases	References
A20	N-terminal ovarian tumor domain responsible for deubiquinating activity. C-terminal domain composed of 7 zinc fingers, which mediate its E3 ubiquitin ligase activity and ubiquitin-binding activity.	RIP1, RIP2, RIP3, TRAF2/TRAF6, NEMO, MALT1, UBC13	Restricts NF-κB signaling downstream of TNFR, TCR, TLR, NLR, and IL-1R	Periodontitis, SLE, rheumatoid arthritis, psoriasis, type 1 diabetes, Crohn disease, coronary artery disease in type 2 diabetes, systemic sclerosis, Behçet disease, Sjögren syndrome, diffuse large B-cell lymphoma, mucosa-associated lymphoid tissue-type lymphoma, Hodgkin lymphoma, neurological disorders, cystic fibrosis, asthma, haploinsufficiency of A20, cancers	Ma and Malynn (2012), Zhou et al. (2016), Crump et al. (2017), Aeschlimann et al. (2018), Malynn and Ma (2019), Martens and van Loo (2020)
CYLD	Three cytoskeletal-associated protein-glycine-conserved (CAP-Gly) repeats and 1 ubiquitin-specific protease domain that mediates its deubiquitinating activity	TRAF2/TRAF6, NEMO, RIP1, TAK1	Negatively regulates NF-κB signaling upstream of IKK	Cylindromatosis, multiple familial trichoepithelioma, Brook-Spiegler syndrome, multiple myeloma, cancers	Hu and Sun (2016), Rothschild et al. (2018)
Cezanne	N-terminal domain responsible for its deubiqutinating activity and a C-terminal domain that mediates its ubiquitin-binding activity	RIP1, TRAF3, TRAF6	Restricts NF-κB activation upstream of IKK complex	Cancers	Hu and Sun (2016), Rothschild et al. (2018)

IKK, IκB kinase complex; IL-1R, interleukin 1 receptor; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein; NEMO, NF-κB essential modulator; RIP, receptor interacting protein; SLE, systemic lupus erythematosus; TAK1, TGFβ-activated kinase 1; TCR, T-cell receptor; TLR, Toll-like receptor; TNFR, tumor necrosis factor receptor; TRAF, TNF receptor-associated factor; UBC13, ubiquitin-conjugating 13.