Chaperone-mediated autophagy contributes to chromosomal stability by controlling TTC28 degradation

While macroautophagy (autophagy) contributes to maintaining chromosomal stability via multiple pathways, including regulating chromatin ubiquitination and cytoplasmic DNA fragment degradation, the impacts of microautophagy and chaperone-mediated autophagy (CMA) on maintaining chromosomal stability are not known. The TTC28 (tetratricopeptide repeat domain 28) gene is frequently mutated and downregulated in human cancers. The molecular mass of the TTC28 protein is 271 kDa, which makes its functional study very difficult. Recently, we reported that TTC28 plays a key role in maintaining chromosomal stability, probably through regulating mitosis and cytokinesis, and that TTC28 downregulation may contribute to the high chromosomal instability (CIN) of cancer cells, according to the results of serial experiments and bioinformatics analyses. Notably, our findings demonstrate that TTC28 is a substrate of CMA and microautophagy and that these pathways also play a role in maintaining chromosomal stability in a TTC28-dependent manner. These findings demonstrate that CMA- and microautophagy-mediated degradation is a master regulator of the ability of TTC28 to maintain genome stability.