Ubiquitin specific peptidase 18 (USP18), previously known as UBP43, is the IFN-stimulated gene 15 (ISG15) deconjugase. USP18 removes ISG15 from substrate
proteins. This study reports that USP18-null mice (vs. wild-type mice) exhibited lower lipolysis rates, altered fat to
body weight ratios, and cold sensitivity. USP18 is a regulator of
lipid and
fatty acid metabolism. Prior work established that USP18 promotes lung
tumorigenesis. We sought to learn whether this occurs through altered
lipid and
fatty acid metabolism. Loss of USP18 repressed adipose
triglyceride lipase (ATGL) expression; gain of USP18 expression upregulated ATGL in
lung cancer cells. The E1-like
ubiquitin activating enzyme promoted ISG15 conjugation of ATGL and destabilization. Immunoprecipitation assays confirmed that ISG15 covalently conjugates to ATGL.
Protein expression of thermogenic regulators was examined in brown fat of USP18-null versus wild-type mice.
Uncoupling protein 1 (UCP1) was repressed in USP18-null fat. Gain of USP18 expression augmented
UCP1 protein via reduced ubiquitination. Gain of UCP1 expression in
lung cancer cell lines enhanced cellular proliferation. UCP1 knockdown inhibited proliferation.
Beta-hydroxybutyrate colorimetric assays performed after gain of UCP1 expression revealed increased cellular
fatty acid beta-oxidation, augmenting
fatty acid beta-oxidation in Seahorse assays. Combined USP18, ATGL, and UCP1 profiles were interrogated in The
Cancer Genome Atlas. Intriguingly,
lung cancers with increased USP18, ATGL, and UCP1 expression had an unfavorable survival. These findings reveal that USP18 is a pharmacologic target that controls
fatty acid metabolism. IMPLICATIONS: USP18 is an
antineoplastic target that affects
lung cancer fatty acid metabolism.