ubiquitin carboxyl-terminal hydrolase CYLD; deubiquitinating enzyme CYLD; ubiquitin thiolesterase CYLD; ubiquitin-specific-processing protease CYLD (CYLD, CYLD1, KIAA0849, HSPC057)

Function

• protease
• specifically cleaves Lys-63-linked polyubiquitin chains
• has endodeubiquitinase activity
• role in regulation of pathways leading to NF-kappa-B activation
• contributes to regulation of cell survival, proliferation & differentiation via its effects on NF-kappa-B activation
• negative regulator of Wnt signaling
• inhibits HDAC6 & thus promotes acetylation of alpha-tubulin & stabilization of microtubules
• role in regulation of microtubule dynamics, & thus contributes to regulation of cell proliferation, cell polarization, cell migration, & angiogenesis
• required for normal cell cycle progress & normal cytokinesis
• inhibits nuclear translocation of NF-kappa-B
• role in inflammation & the innate immune response, via its effects on NF-kappa-B activation
• role in maturation of natural killer cells (NK cells)
  • dispensable for maturation of intrathymic NK cells
  • required for continued survival of immature NK cells
• negatively regulates TNFRSF11A signaling & genesis of osteoclasts (putative)
• thiol-dependent hydrolysis of ester, thioester, amide, peptide & isopeptide bonds formed by the C-terminal Gly of ubiquitin
• inhibited by phosphorylation at Ser
• phosphorylated on several Ser by IKKA &/or IKKB in response to immune stimuli
• phosphorylation requires IKBKG
• phosphorylation abolishes TRAF2 deubiquitination, interferes with activation of Jun kinases, & strongly reduces CD40-dependent gene activation by NF-kappa-B
• interacts (via CAP-Gly domain) with IKBKG/NEMO (via proline-rich C-terminal region)
• interacts with TRAF2 & TRIP
• interacts with PLK1, DVL1, DVL3, MAVS, TBK1, IKKE & DDX58
• interacts (via CAP-Gly domain) with microtubules
• interacts with HDAC6 & BCL3
• interacts with SQSTM1 & MAP3K7
• identified in a complex with TRAF6 & SQSTM1 (putative)

Structure

• belongs to the peptidase C67 family
• contains 3 CAP-Gly domains

Compartment

• cytoplasm, perinuclear region, cytoskeleton
• plasma membrane, cytoplasmic side
• associates with microtubule cytoskeleton during interphase
• associated with midbody during telophase

Alternative splicing

named isoforms=2

Expression

• expressed in fetal brain, testis, & skeletal muscle
• lower expression in adult brain, leukocytes, liver, heart, kidney, spleen, ovary & lung
• isoform 2 is found in all tissues except kidney

Pathology

• defects in CYLD are the cause of
  • familial cylindromatosis
  • multiple familial trichoepithelioma type 1
  • Brooke-Spiegler syndrome

More general terms

• ubiquitin C-terminal hydrolase
• metalloprotein
• oligomerizing protein
• phosphoprotein

Additional terms

• familial cylindromatosis; Ancell-Spiegler cylindromas; dermal eccrine cylindromatosis; turban tumor syndrome
• ubiquitin (UBCEP2, UBB, UBC)

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=1540
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:1540
• OMIM: https://mirror.omim.org/entry/132700
• OMIM: https://mirror.omim.org/entry/601606
• OMIM: https://mirror.omim.org/entry/605018
• OMIM: https://mirror.omim.org/entry/605041
• UniProt: http://www.uniprot.org/uniprot/Q9NQC7.html