ACOT8

ACOT8 is an acyl-CoA thioesterase that modulates cellular fatty acid levels, particularly palmitate, and through this metabolic activity influences inflammation and tumor cell behavior (PMID:41905213). In renal tubular epithelial cells, elevated ACOT8 during ischemia-reperfusion injury drives palmitate accumulation that activates the cGAS-STING pathway in macrophages, promoting M1 polarization and renal inflammation; tubule-specific ACOT8 knockdown reduces palmitate accumulation, M1 infiltration, and improves renal function (PMID:41905213). ACOT8 protein stability is supported by physical interaction with TSC22D2, and TSC22D2-driven ACOT8 expression restrains colorectal cancer proliferation and metastasis via an EMT-related mechanism (PMID:38476309). ACOT8 also physically engages HIV-1 Nef through defined surface regions (Arg45-Phe55, Arg86-Pro93, with Lys91 as a key residue), an interaction that may preserve Nef from degradation (PMID:26927806). Beyond these contexts, the enzymatic mechanism and structural basis of ACOT8 thioesterase activity have not been characterized in the available corpus.

1. 2016 Medium

   Established that ACOT8 is a physical binding partner of HIV-1 Nef and mapped the specific surface determinants of that interaction, raising the possibility that ACOT8 stabilizes Nef.

   Evidence In silico structural modelling, reciprocal co-immunoprecipitation, immunofluorescence, and ACOT8 deletion/point mutant analysis

   PMID:26927806

   Open questions at the time

   • Functional consequence of Nef stabilization for viral replication not demonstrated
   • No direct measurement of ACOT8 thioesterase activity in the Nef-bound state
   • Interaction shown in a single lab without independent replication
2. 2024 Medium

   Identified TSC22D2 as a physical partner that maintains ACOT8 protein stability, linking ACOT8 levels to suppression of colorectal cancer proliferation and metastasis.

   Evidence Co-IP/mass spectrometry interaction mapping with knockdown/overexpression functional assays and an in vivo mouse model

   PMID:38476309

   Open questions at the time

   • Mechanism by which TSC22D2 stabilizes ACOT8 (e.g. blocking degradation) not defined
   • Whether ACOT8 thioesterase activity is required for the anti-EMT effect untested
   • Direct interaction not confirmed by reciprocal or in vitro binding
3. 2026 Medium

   Placed ACOT8 in an inflammatory signaling axis by showing its activity drives palmitate accumulation that activates macrophage cGAS-STING and M1 polarization during renal ischemia-reperfusion injury.

   Evidence In vivo AAV9 tubule-specific knockdown in a mouse IRI model with single-cell RNA-seq, lipidomics, and in vitro experiments

   PMID:41905213

   Open questions at the time

   • Direct enzymatic link between ACOT8 and palmitate generation not biochemically demonstrated
   • Mechanism of palmitate transfer from tubular cells to macrophages unclear
   • Generalizability beyond the IRI model not established

• The intrinsic biochemical substrate specificity, catalytic mechanism, and structural basis of ACOT8 thioesterase activity remain to be directly defined.
• No in vitro reconstitution of substrate range reported
• No structural model of the active site
• Unclear how ACOT8 activity is regulated across the distinct contexts (Nef, TSC22D2, IRI)