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

Tumor suppressors represent one of the first lines of defense against malignant transformation and their inactivation in cells leads to onset of tumorigenesis. Cancer cells employ a variety of ways to inactivate cellular tumor suppressors, such as their epigenetic silencing or mutagenesis. Less understood are mechanisms by which cancer cells inactivate tumor suppressors post-translationally. Here, we uncovered a previously undescribed post-translational strategy that cancer cells use to inactivate the potent mitochondrial tumor suppressor LACTB in breast cancers. We discovered that substrate of LACTB can be LACTB itself; that LACTB possesses autoproteolytic ability, which is important for the modulation of its tumor suppressor activity. We show that cancer cells misuse this feature of LACTB to force LACTB into self-degradation. This is mechanistically realized through upregulation of mitochondrial MRPS34 protein, which, through interaction with LACTB, is a positive regulator of the autoproteolytic activity of LACTB and a negative regulator of LACTB. This study, through in vitro, in vivo, human clinical tumor samples and mutagenesis, provides important new insights into how cancer cells fine-tune the expression and activity of tumor suppressors to promote tumorigenesis. Statement of SignificanceWe uncovered a unique post-translational strategy and mechanism cancer cells employ to inactivate the potent mitochondrial tumor suppressor LACTB in breast cancers thus expanding our knowledge on regulatory and adaptive mechanisms cancer cells use to silence tumor suppressors.