bims-lypmec 2023-04-02 papers

Issue of 2023‒04‒02
three papers selected by
Satoru Kobayashi
New York Institute of Technology

Cell Death Differ. 2023 Mar 30.

Epigenetic regulation of autophagy by histone-modifying enzymes under nutrient stress.

Young Suk Yu, Hyunkyung Kim, Keun Il Kim, Sung Hee Baek.

Autophagy is an evolutionarily conserved catabolic process that is induced in response to various stress factors in order to protect cells and maintain cellular homeostasis by degrading redundant components and dysfunctional organelles. Dysregulation of autophagy has been implicated in several conditions such as cancer, neurodegenerative diseases, and metabolic disorders. Although autophagy has been commonly considered as a cytoplasmic process, accumulating evidence has revealed that epigenetic regulation within the nucleus is also important for regulation of autophagy. In particular, when energy homeostasis is disrupted, for instance due to nutrient deprivation, cells increase autophagic activity at the transcriptional level, thereby also increasing the extent of overall autophagic flux. The transcription of genes associated with autophagy is strictly regulated by epigenetic factors through a network of histone-modifying enzymes along with histone modifications. A better understanding of the complex regulatory mechanisms of autophagy could reveal potential new therapeutic targets for autophagy-related diseases. In this review, we discuss the epigenetic regulation of autophagy in response to nutrient stress, focusing on histone-modifying enzymes and histone modifications.

DOI: https://doi.org/10.1038/s41418-023-01154-9

EMBO J. 2023 Mar 27. e111241

TFEB-dependent lysosome biogenesis is required for senescence.

Rachel Curnock, Katy Yalci, Johan Palmfeldt, Marja Jäättelä, Bin Liu, Bernadette Carroll.

The accumulation of senescent cells is recognised as a driver of tissue and organismal ageing. One of the gold-standard hallmarks of a senescent cell is an increase in lysosomal content, as measured by senescence-associated β-galactosidase (Senβ-Gal) activity. The lysosome plays a central role in integrating mitogenic and stress cues to control cell metabolism, which is known to be dysregulated in senescence. Despite this, little is known about the cause and consequence of lysosomal biogenesis in senescence. We find here that lysosomes in senescent cells are dysfunctional; they have higher pH, increased evidence of membrane damage and reduced proteolytic capacity. The significant increase in lysosomal content is however sufficient to maintain degradative capacity of the cell to a level comparable to proliferating control cells. We demonstrate that increased nuclear TFEB/TFE3 supports lysosome biogenesis, is a hallmark of multiple forms of senescence and is required for senescent cell survival. TFEB/TFE3 are hypo-phosphorylated and show constitutive nuclear localisation in senescence. Evidence suggests that several pathways may contribute to TFEB/TFE3 dysregulation in senescence.

Keywords: TFEB; autophagy; lysosome; senescence

DOI: https://doi.org/10.15252/embj.2022111241

Adv Exp Med Biol. 2023 ;1422 193-215

Role of Lysosomal Cholesterol in Regulating PI(4,5)P2-Dependent Ion Channel Function.

Eamonn J Dickson.

Lysosomes are central regulators of cellular growth and signaling. Once considered the acidic garbage can of the cell, their ever-expanding repertoire of functions include the regulation of cell growth, gene regulation, metabolic signaling, cell migration, and cell death. In this chapter, we detail how another of the lysosome's crucial roles, cholesterol transport, plays a vital role in the control of ion channel function and neuronal excitability through its ability to influence the abundance of the plasma membrane signaling lipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). This chapter will introduce the biosynthetic pathways of cholesterol and PI(4,5)P2, discuss the molecular mechanisms through which each lipid distinctly regulates ion channels, and consider the interdependence of these lipids in the control of ion channel function.

Keywords: Cholesterol; Ion channels; Niemann Pick Type C; PI(4,5)P2; Phosphoinositides; lysosome

DOI: https://doi.org/10.1007/978-3-031-21547-6_7