The role of autoproteolysis and mitoribosomal proteins in the regulation of the mitochondrial LACTB tumor suppressor.

Tumor suppressors represent one of the first lines of defense against malignant transformation, and their inactivation in cells leads to the onset of tumorigenesis. Cancer cells employ various mechanisms to inactivate cellular tumor suppressors, including epigenetic silencing and mutagenesis. Less understood are the mechanisms by which cancer cells inactivate tumor suppressors post-translationally. Here, we uncovered a previously undescribed post-translational mechanism by which cancer cells inactivate the potent mitochondrial tumor suppressor LACTB in breast cancers. We discovered that the substrate of LACTB can be LACTB itself; LACTB possesses autoproteolytic activity, which is important for modulating its tumor suppressor activity. We demonstrate that cancer cells exploit this feature of LACTB to induce LACTB's self-degradation. This is mechanistically realized through upregulation of mitochondrial MRPS34 protein, which, through interaction with LACTB, is a positive regulator of LACTB's autoproteolytic activity and a negative regulator of LACTB. This study provides insights into how cancer cells fine-tune the expression and activity of tumor suppressors to promote tumorigenesis.