YDJC

YDJC is a metal-dependent deacetylase whose catalytic architecture is defined by an Asp-His-His metal-binding triad conserved across the YdjC family, originally resolved in the (βα)-barrel fold of the bacterial homolog TTHB029 and shown to resemble peptidoglycan N-acetylglucosamine deacetylase (PMID:18177738). The enzymatic identity of this family is established by bacterial members that deacetylate carbohydrate and lipid substrates: ChbG deacetylates chitooligosaccharide phosphates, an activity abolished by metal-binding residue substitution (PMID:22797760), and NaxD deacetylates lipid A-linked galactosamine (PMID:22966934). In human cells YDJC acts as a catalytically active deacetylase with substrate specificity extending to proteins: in CD4+ T cells it directly deacetylates SREBP2 to suppress cholesterol biosynthesis gene expression (Hmgcr, Hmgcs1, Cyp51), restraining T cell proliferation and Th1 differentiation, with Ydjc loss exacerbating colitis through unrestrained SREBP2-driven cholesterol synthesis (PMID:41162693). In lung cancer cells, YDJC binds CDC16 and, in a manner dependent on its catalytic Asp13 residue, drives ERK activation, keratin 8 phosphorylation and perinuclear reorganization, PP2A ubiquitination, and epithelial-mesenchymal transition, with CDC16 itself promoting YDJC ubiquitination to suppress EMT (PMID:29796162, PMID:31485224).

1. 2008 High

   Established the structural and catalytic identity of the YdjC family by resolving the fold and active site, framing human YDJC as a putative metal-dependent deacetylase before any direct human assay existed.

   Evidence X-ray crystallography of T. thermophilus TTHB029 at 2.9 Å with structural comparison to a peptidoglycan deacetylase

   PMID:18177738

   Open questions at the time

   • No human YDJC structure determined
   • Substrate of the human enzyme not addressed by structure alone
2. 2012 High

   Demonstrated that the conserved active site is genuinely catalytic by showing bacterial homologs deacetylate defined substrates, validating the predicted metal-binding triad through loss-of-function mutagenesis.

   Evidence ChbG growth/genetic-epistasis assays on chitooligosaccharides and NaxD enzymatic and mass-spectrometry assays on lipid A in bacteria

   PMID:22797760 PMID:22966934

   Open questions at the time

   • Substrates are bacterial carbohydrate/lipid species, not human targets
   • Does not establish human YDJC activity directly
3. 2018 Medium

   First linked human YDJC catalytic activity to a cellular phenotype, showing a binding partner and that the deacetylase active site is required for promoting oncogenic signaling and motility.

   Evidence Co-IP with CDC16, siRNA, overexpression of wild-type versus YDJCD13A catalytic mutant, ERK phosphorylation and migration/invasion assays in A549 cells

   PMID:29796162

   Open questions at the time

   • No in vitro reconstitution of catalysis
   • Direct enzymatic substrate in this context not identified
   • CDC16 interaction validated by single Co-IP
4. 2019 Medium

   Extended the lung cancer mechanism by tying YDJC catalytic activity to PP2A ubiquitination and EMT, and positioned CDC16 as a regulator that ubiquitinates YDJC to suppress these effects.

   Evidence Wild-type versus YDJCD13A overexpression, ubiquitination assays, EMT marker immunoblotting, and orthotopic mouse model

   PMID:31485224

   Open questions at the time

   • Mechanistic link between deacetylase activity and PP2A ubiquitination not reconstituted
   • Direct deacetylation substrate not defined in this system
5. 2025 High

   Identified a direct protein substrate of human YDJC by showing it deacetylates SREBP2 to restrain cholesterol biosynthesis and Th1 differentiation, providing the strongest direct enzyme-substrate evidence in a mammalian context.

   Evidence Ydjc-/- mouse model, direct SREBP2 deacetylation assay, integrative omics, and genetic/pharmacological cholesterol-pathway rescue in colitis models

   PMID:41162693

   Open questions at the time

   • Acetylation site(s) on SREBP2 and structural basis of recognition not defined
   • Relationship between the T cell SREBP2 substrate and the lung cancer PP2A/ERK mechanism unresolved

• How a single deacetylase active site discriminates between carbohydrate-derived substrates (bacterial homologs) and protein substrates such as SREBP2, and how its activity intersects with the CDC16-dependent ubiquitination axis, remains unresolved.
• No unified biochemical model of human YDJC substrate specificity
• No structure of human YDJC bound to a substrate
• Tissue-context determinants of T cell versus epithelial function unknown