bims-apauto 2022-12-11 papers

Issue of 2022–12–11
four papers selected by
Su Hyun Lee, Seoul National University

Nat Commun. 2022 Dec 06. 13(1): 7526

SESAME-catalyzed H3T11 phosphorylation inhibits Dot1-catalyzed H3K79me3 to regulate autophagy and telomere silencing.

Fei He, Qi Yu, Min Wang, Rongsha Wang, Xuanyunjing Gong, Feng Ge, Xilan Yu, Shanshan Li.

The glycolytic enzyme, pyruvate kinase Pyk1 maintains telomere heterochromatin by phosphorylating histone H3T11 (H3pT11), which promotes SIR (silent information regulator) complex binding at telomeres and prevents autophagy-mediated Sir2 degradation. However, the exact mechanism of action for H3pT11 is poorly understood. Here, we report that H3pT11 directly inhibits Dot1-catalyzed H3K79 tri-methylation (H3K79me3) and uncover how this histone crosstalk regulates autophagy and telomere silencing. Mechanistically, Pyk1-catalyzed H3pT11 directly reduces the binding of Dot1 to chromatin and inhibits Dot1-catalyzed H3K79me3, which leads to transcriptional repression of autophagy genes and reduced autophagy. Despite the antagonism between H3pT11 and H3K79me3, they work together to promote the binding of SIR complex at telomeres to maintain telomere silencing. Furthermore, we identify Reb1 as a telomere-associated factor that recruits Pyk1-containing SESAME (Serine-responsive SAM-containing Metabolic Enzyme) complex to telomere regions to phosphorylate H3T11 and prevent the invasion of H3K79me3 from euchromatin into heterochromatin to maintain telomere silencing. Together, these results uncover a histone crosstalk and provide insights into dynamic regulation of silent heterochromatin and autophagy in response to cell metabolism.

DOI: https://doi.org/10.1038/s41467-022-35182-9

Autophagy. 2022 Dec 05.

Regulation of autophagosome biogenesis and mitochondrial bioenergetics by the cholesterol transport protein GRAMD1C.

Chara Charsou, Matthew Yoke Wui Ng, Anne Simonsen.

Autophagosomes are crucial components of the cellular recycling machinery that form at endoplasmic reticulum (ER)-associated sites. As the autophagosome membrane is largely devoid of transmembrane proteins, autophagosome biogenesis is thought to be largely regulated by lipid transfer and lipid modifications, as well as membrane-associated proteins. While the membrane origin of autophagosomes and their lipid composition are still incompletely understood, previous studies have found the autophagosome membrane to be enriched in unsaturated fatty acids and have little cholesterol, suggesting that cholesterol removal is an integral step during autophagosome biogenesis. In our study, we demonstrate that short term cholesterol depletion leads to a rapid induction of autophagy and identify the ER-localized cholesterol transport protein GRAMD1C as a negative regulator of starvation-induced macroautophagy/autophagy.

Keywords: Aster; GRAMD1C; VASt; autophagy; ccRCC; cholesterol

DOI: https://doi.org/10.1080/15548627.2022.2155020

Autophagy. 2022 Dec 06.

Autophagy Inhibition Signals through Senescence to Promote Tumor Suppression.

Nanfang Peng, Helen H Kang, Yan Feng, Alexander M Minikes, Xuejun Jiang.

Macroautophagy/autophagy, a stress-responsive cellular survival mechanism, plays important and context-dependent roles in cancer, and its inhibition has been implicated as a promising cancer therapeutic approach. The detailed mechanisms underlying the function of autophagy in cancer have not been fully understood. In this study, we show that autophagy inhibition promotes both the efficacy of chemotherapy for the treatment of glioblastoma (GBM) and therapy-induced senescence of GBM cells. As a specific cell fate characterized by permanent cell cycle arrest, senescence is also associated with the expression of a panel of specific secreted protein factors known as senescence-associated secretory phenotype (SASP). Intriguingly, we found that autophagy inhibition not only quantitatively enhanced GBM cell senescence but also qualitatively altered the spectrum of SASP. The altered SASP had increased potent activity to induce paracrine senescence of neighboring GBM cells, to skew macrophage polarization toward the anti-tumor M1 state, and to block the recruitment of pro-tumor neutrophils to GBM tumor tissues. Taken together, this study reveals novel functional communication between autophagy and senescence and suggests cancer therapeutic approaches harnessing autophagy blockage in inducing senescence-mediated antitumor immunity.

Keywords: SASP; antitumor immunity; autophagy; glioblastoma multiform; senescence

DOI: https://doi.org/10.1080/15548627.2022.2155794

Nat Commun. 2022 Dec 08. 13(1): 7583

Divergent self-association properties of paralogous proteins TRIM2 and TRIM3 regulate their E3 ligase activity.

Diego Esposito, Jane Dudley-Fraser, Acely Garza-Garcia, Katrin Rittinger.

Tripartite motif (TRIM) proteins constitute a large family of RING-type E3 ligases that share a conserved domain architecture. TRIM2 and TRIM3 are paralogous class VII TRIM members that are expressed mainly in the brain and regulate different neuronal functions. Here we present a detailed structure-function analysis of TRIM2 and TRIM3, which despite high sequence identity, exhibit markedly different self-association and activity profiles. We show that the isolated RING domain of human TRIM3 is monomeric and inactive, and that this lack of activity is due to a few placental mammal-specific amino acid changes adjacent to the core RING domain that prevent self-association but not E2 recognition. We demonstrate that the activity of human TRIM3 RING can be restored by substitution with the relevant region of human TRIM2 or by hetero-dimerization with human TRIM2, establishing that subtle amino acid changes can profoundly affect TRIM protein activity. Finally, we show that TRIM2 and TRIM3 interact in a cellular context via their filamin and coiled-coil domains, respectively.

DOI: https://doi.org/10.1038/s41467-022-35300-7