The telomeric protein TERF2/TRF2 impairs HMGB1-driven autophagy

TERF2/TRF2 is a pleiotropic telomeric protein that plays a crucial role in tumor formation andprogression through several telomere-dependent and -independent mechanisms. Here, we uncov-ered a novel function for this protein in regulating the macroautophagic/autophagic process upondifferent stimuli. By using both biochemical and cell biology approaches, we found that TERF2 bindsto the non-histone chromatin-associated protein HMGB1, and this interaction is functional to thenuclear/cytoplasmic protein localization. Specifically, silencing of TERF2 alters the redox status of thecells, further exacerbated upon EBSS nutrient starvation, promoting the cytosolic translocation andthe autophagic activity of HMGB1. Conversely, overexpression of wild-type TERF2, but not the mutantunable to bind HMGB1, negatively affects the cytosolic translocation of HMGB1, counteracting thestimulatory effect of EBSS starvation. Moreover, genetic depletion of HMGB1 or treatment withinflachromene, a specific inhibitor of its cytosolic translocation, completely abolished the pro-autophagic activity of TERF2 silencing. In conclusion, our data highlighted a novel mechanismthrough which TERF2 modulates the autophagic process, thus demonstrating the key role of thetelomeric protein in regulating a process that is fundamental, under both physiological and patho-logical conditions, in defining the fate of the cells.