The telomeric protein TERF2/TRF2 impairs HMGB1-driven autophagy

Abstract

TERF2/TRF2 is a pleiotropic telomeric protein that plays a crucial role in tumor formation and progression through several telomere-dependent and -independent mechanisms. Here, we uncovered a novel function for this protein in regulating the macroautophagic/autophagic process upon different stimuli. By using both biochemical and cell biology approaches, we found that TERF2 binds to the non-histone chromatin-associated protein HMGB1, and this interaction is functional to the nuclear/cytoplasmic protein localization. Specifically, silencing of TERF2 alters the redox status of the cells, further exacerbated upon EBSS nutrient starvation, promoting the cytosolic translocation and the autophagic activity of HMGB1. Conversely, overexpression of wild-type TERF2, but not the mutant unable to bind HMGB1, negatively affects the cytosolic translocation of HMGB1, counteracting the stimulatory effect of EBSS starvation. Moreover, genetic depletion of HMGB1 or treatment with inflachromene, a specific inhibitor of its cytosolic translocation, completely abolished the pro-autophagic activity of TERF2 silencing. In conclusion, our data highlighted a novel mechanism through which TERF2 modulates the autophagic process, thus demonstrating the key role of the telomeric protein in regulating a process that is fundamental, under both physiological and pathological conditions, in defining the fate of the cells. Abbreviations: ALs: autolysosomes; ALT: alternative lengthening of telomeres; ATG: autophagy related; ATM: ATM serine/threonine kinase; CQ: Chloroquine; DCFDA: 2’,7’-dichlorofluorescein diacetate; DDR: DNA damage response; DHE: dihydroethidium; EBSS: Earle’s balanced salt solution; FACS: fluorescence-activated cell sorting; GFP: green fluorescent protein; EGFP: enhanced green fluorescent protein; GSH: reduced glutathione; GSSG: oxidized glutathione; HMGB1: high mobility group box 1; ICM: inflachromene; IF: immunofluorescence; IP: immunoprecipitation; NAC: N-acetyl-L-cysteine; NHEJ: non-homologous end joining; PLA: proximity ligation assay; RFP: red fluorescent protein; ROS: reactive oxygen species; TIF: telomere-induced foci; TERF2/TRF2: telomeric repeat binding factor 2.

miR-29b-1-5p exacerbates myocardial injury induced by sepsis in a mouse model by targeting TERF2

“…During autophagy, depletion of TERF2 promotes autophagy [57]. Lachettini et al [58] reported that TERF2 knockdown induces autophagy by sequestering HMGB1 into the nucleus, where it exerts its pro-autophagic effect when it is shuttled from the nucleus to the cytosol [59]. Moreover, inhibition of TERF2 leads to autophagic death, and apoptosis has also been proven to occur in gastric cancer [60].…”

Univariable and multivariable Mendelian randomization investigating the effects of telomere length on the risk of adverse pregnancy outcomes

“…This suggests that the downregulation of TERF2/TRF2 expression results in telomere uncapping, which plays a crucial role in pregnancy loss (66). Other studies have demonstrated that TERF2 can regulate autophagy by binding to High Mobility Group Box 1 (HMGB1), a non-histone Chromatin-related protein (67). In recent years, a large number of studies have suggested that abnormalities in autophagy may be associated with SA by modulating decidualization, trophoblast cells, and immune cells at the maternal fetal interface (68).…”

Testosterone Exacerbates the Formation of Liver Cancer Induced by Environmental N-Nitrosamines Exposure: Potential Mechanisms and Implications for Human Health

“…The high mobility group box 1 protein (HMGB1), expressed ubiquitously in the nucleus of almost all eukaryotic cells, interacts with nucleosomes, transcription factors, and histones to regulate DNA replication, repair, recombination, and transcription. 31 After phosphorylation and acetylation, HMGB1 is translocated into the cytosol 32 and subsequently secreted into the intercellular space as an inflammatory cytokine mediator. 33 HMGB1 has been shown to be associated with the activation of cancer-related transcription factors p53, p73, and NF-κB in the nucleus, promoting the invasion of cancer cells.…”