NAA38

NAA38 is the small auxiliary subunit of the trimeric NatC N-terminal acetyltransferase complex, which acts co-translationally at the ribosome together with the catalytic subunit NAA30 and the auxiliary subunit NAA35 to acetylate the N-termini of substrate proteins (PMID:34019809, PMID:29247799). All three subunits are required for full NatC activity, and the assembled complex is stabilized by tightly bound inositol hexaphosphate (IP6) (PMID:34019809). Structurally, NAA38 contributes to catalytic competence by ordering an N-terminal segment of NAA35 and reorienting an NAA30 peptide-binding loop, which increases the thermostability of human NatC and broadens its substrate-specificity profile (PMID:36638802). Beyond its core acetyltransferase role, loss of NAA38 function stabilizes the transcription factor NRF2 through the KEAP1-NRF2 pathway and raises intracellular glutathione, although this only weakly protects against ferroptosis because NRF2 also drives MRP1-mediated glutathione efflux (PMID:30726737). NatC activity is induced by ATF6-branch ER stress and, through sustaining cathepsin K (CTSK) protein levels that drive proteolysis of insulin receptor substrate 1, promotes muscle atrophy in cancer cachexia (PMID:41852114).

1. 2017 Medium

   Established NAA38 as an auxiliary subunit of the NatC complex and placed its activity in the co-translational N-terminal acetylation context, defining the functional unit within which NAA38 operates.

   Evidence In vitro N-terminal acetyltransferase activity assays with peptide substrates and NatC subunit characterization

   PMID:29247799

   Open questions at the time

   • Does not resolve the specific structural contribution of NAA38 versus the catalytic NAA30 subunit
   • Single-lab in vitro characterization without structural detail
2. 2019 Medium

   Connected NAA38 loss to redox homeostasis, showing that disruption stabilizes NRF2 and elevates glutathione, linking the acetyltransferase machinery to ferroptosis sensitivity.

   Evidence Genome-wide haploid genetic screen with FACS sorting for glutathione and ferroptosis viability assays

   PMID:30726737

   Open questions at the time

   • Mechanistic link to NAA38 is indirect, derived from a loss-of-function screen rather than a defined molecular intermediate
   • How NatC activity feeds into the KEAP1-NRF2 axis is not defined
   • Does not identify the NatC substrate(s) responsible for the phenotype
3. 2021 High

   Resolved the architecture of NatC and showed all three subunits are required for normal activity, while identifying IP6 as a structural cofactor stabilizing the complex.

   Evidence Cryo-EM structure of S. pombe NatC with a bisubstrate analog plus biochemical activity assays

   PMID:34019809

   Open questions at the time

   • Performed in S. pombe; the specific role of NAA38 within the human complex was not isolated
   • Functional consequence of IP6 binding for catalysis not fully dissected
4. 2023 High

   Directly attributed thermostabilization and substrate-specificity broadening of human NatC to NAA38 by comparing structures with and without the subunit, defining its mechanistic contribution.

   Evidence Cryo-EM structures of human NatC ±NAA38 with thermostability and substrate-specificity biochemical assays

   PMID:36638802

   Open questions at the time

   • Full repertoire of substrates broadened by NAA38 in vivo not enumerated
   • Cellular consequences of NAA38-dependent substrate broadening not established
5. 2026 Medium

   Linked NatC activity to ER-stress resistance and cancer cachexia, showing ATF6-branch UPR induces NatC, which sustains cathepsin K to drive IRS1 proteolysis and muscle atrophy.

   Evidence Genome-wide CRISPR screen in ER-stress context, in vivo shRNA knockdown in a mouse LLC cachexia model, western blotting, and ATF6 pharmacology

   PMID:41852114

   Open questions at the time

   • Phenotype attributed to the whole NatC complex rather than NAA38 specifically
   • Whether cathepsin K stabilization depends on direct N-terminal acetylation is not established
   • Mechanism by which ATF6 signaling upregulates NatC is undefined

• The in vivo substrate repertoire of NAA38-containing NatC and the causal chain linking its acetyltransferase activity to the NRF2/glutathione and cathepsin K phenotypes remain to be defined.
• No NatC substrate has been mechanistically tied to either the ferroptosis or cachexia phenotype
• Whether the downstream effects are acetylation-dependent is unresolved