bims-meprid 2023-02-19 papers

Proc Natl Acad Sci U S A. 2023 Feb 21. 120(8): e2213272120

Cytoskeletal association of ATP citrate lyase controls the mechanodynamics of macropinocytosis.

Joseph Puccini, Jia Wei, Liang Tong, Dafna Bar-Sagi.

Macropinocytosis is an actin-dependent mode of nonselective endocytosis that mediates the uptake of extracellular fluid-phase cargoes. It is now well recognized that tumor cells exploit macropinocytosis to internalize macromolecules that can be catabolized and used to support cell growth and proliferation under nutrient-limiting conditions. Therefore, the identification of molecular mechanisms that control macropinocytosis is fundamental to the understanding of the metabolic adaptive landscape of tumor cells. Here, we report that the acetyl-CoA-producing enzyme, ATP citrate lyase (ACLY), is a key regulator of macropinocytosis and describes a heretofore-unappreciated association of ACLY with the actin cytoskeleton. The cytoskeletal tethering of ACLY is required for the spatially defined acetylation of heterodimeric actin capping protein, which we identify as an essential mediator of the actin remodeling events that drive membrane ruffling and macropinocytosis. Furthermore, we identify a requirement for mitochondrial-derived citrate, an ACLY substrate, for macropinocytosis, and show that mitochondria traffic to cell periphery regions juxtaposed to plasma membrane ruffles. Collectively, these findings establish a mode of metabolite compartmentalization that supports the spatiotemporal modulation of membrane-cytoskeletal interactions required for macropinocytosis by coupling regional acetyl-CoA availability with dynamic protein acetylation.

Keywords: actin cytoskeleton; macropinocytosis; membrane ruffling

DOI: https://doi.org/10.1073/pnas.2213272120

Adv Nutr. 2022 Sep;pii: S2161-8313(23)00037-6. [Epub ahead of print]13(5): 1748-1761

Nutritional Epigenetics in Cancer.

Maria J Barrero, Paloma Cejas, Henry W Long, Ana Ramirez de Molina.

Alterations in the epigenome are well known to affect cancer development and progression. Epigenetics is highly influenced by the environment, including diet, which is a source of metabolic substrates that influence the synthesis of cofactors or substrates for chromatin and RNA modifying enzymes. In addition, plants are a common source of bioactives that can directly modify the activity of these enzymes. Here, we review and discuss the impact of diet on epigenetic mechanisms, including chromatin and RNA regulation, and its potential implications for cancer prevention and treatment.

Keywords: DNA methylation; RNA modifications; bioactives; enhancer; histone modifications; metabolism; obesity

DOI: https://doi.org/10.1093/advances/nmac039

Trends Immunol. 2023 Feb 09. pii: S1471-4906(23)00002-9. [Epub ahead of print]

Metabolism and epigenetics at the heart of T cell function.

Leticia Soriano-Baguet, Dirk Brenner.

T cell subsets adapt and rewire their metabolism according to their functions and surrounding microenvironment. Whereas naive T cells rely on mitochondrial metabolic pathways characterized by low nutrient requirements, effector T cells induce kinetically faster pathways to generate the biomass and energy needed for proliferation and cytokine production. Recent findings support the concept that alterations in metabolism also affect the epigenetics of T cells. In this review we discuss the connections between T cell metabolism and epigenetic changes such as histone post-translational modifications (PTMs) and DNA methylation, as well as the 'extra-metabolic' roles of metabolic enzymes and molecules. These findings collectively point to a new group of potential therapeutic targets for the treatment of T cell-dependent autoimmune diseases and cancers.

Keywords: DNA; NAD; T cells; acetylation; epigentics; histone; metabolism; methylation

DOI: https://doi.org/10.1016/j.it.2023.01.002