Siah E3 ubiquitin protein ligase family member 3 (SIAH3)

Siah E3 ubiquitin protein ligase family member 3 (SIAH3) is an enzyme that belongs to the E3 ubiquitin ligase family, sharing homology with other Seven in absentia proteins (SIAH1, SIAH2) but is structurally distinct and functionally less well characterized. SIAH3 is primarily localized in the mitochondria, where it negatively regulates mitophagy by binding to and destabilizing PINK1, thus inhibiting PRKN (Parkin) recruitment to depolarized mitochondria. This activity makes SIAH3 a physiological suppressor of mitochondrial quality control. In cancer biology, SIAH3 acts as a tumor suppressor and is often epigenetically silenced via hypermethylation in several tumors (e.g., melanoma, lung adenocarcinoma, head and neck cancers), with its reduction correlating to worse prognosis. Overexpression of SIAH3 suppresses cell growth and enhances cell death, in part by shifting cell metabolism from mitochondrial oxidative phosphorylation toward glycolysis and interfering with the translation of mitochondrial proteins. In the nervous system, SIAH3 functions as a negative regulator of mitophagy, with implications for neurodegeneration and axon maintenance. No clinical drugs target SIAH3 directly, but its loss or silencing is considered significant in cancer progression and neurodegenerative conditions.

Other names

Seven in absentia homolog 3Siah-3FLJ39203siah-3

Not applicable/unknown for conventional drugs; SIAH3 functionally interferes with PRKN (Parkin) translocation to mitochondria and with PINK1 stability, thus inhibiting mitophagy.