Large-scale genetic screens identify BET-1 as a cytoskeleton regulator promoting actin health and lifespan

Abstract

The actin cytoskeleton is a three-dimensional scaffold of proteins that is a regulatory, energy-consuming network with dynamic properties to shape the structure and function of the cell. Proper actin function is required for many cellular pathways, including cell division, autophagy, chaperone function, endocytosis, and exocytosis. Deterioration of these processes manifests during aging and exposure to stress, which is in part due to the breakdown of the actin cytoskeleton. However, the regulatory mechanisms involved in preservation of cytoskeletal form and function are not well understood. Here, we performed a multi-pronged, cross-organismal screen combining a whole-genome CRISPR-Cas9 screen in human fibroblasts with in vivo C. elegans synthetic lethality screening. We identified the bromodomain protein, BET-1, as a key regulator of actin health and longevity. Overexpression of bet-1 preserves actin health at late age and promotes lifespan and healthspan in C. elegans. These beneficial effects are mediated through actin preservation by the transcriptional regulator function of BET-1. Together, our discovery assigns a key role for BET-1 in cytoskeletal health, highlighting regulatory cellular networks promoting cytoskeletal homeostasis.

Simple models to understand complex disease: 10 years of progress from Caenorhabditis elegans models of amyotrophic lateral sclerosis and frontotemporal lobar degeneration

“…While C. elegans lack a conserved neuroinflammatory pathway and canonical glia, both important in ALS pathology, previous work in C. elegans has been able to identify a key role for the innate immune response in ALS models. Additionally, glia-like cells in C. elegans have been shown to regulate proteostasis and stress responses in neurons and could be studied in ALS models (Veriepe et al, 2015;Bar-Ziv et al, 2023;Wang et al, 2023b). For abnormal protein conformations and inclusions that slowly develop over time, the short lifespan of C. elegans may not be long enough to observe mature pathological species.…”

“…To directly examine the consequences of human ALS/FTLD genes, researchers can transgenically express wildtype or mutant human disease-associated genes in muscles, neurons, or throughout the C. elegans body, express individual protein domains, or replace the C. elegans homolog with a single-copy knock-in of the wild-type or mutant human gene. More recent efforts to model neurodegenerative diseases in C. elegans have included the development of a photoconvertible fluorescent protein tag to track protein dynamics in vivo (Pigazzini and Kirstein, 2020), the conditional expression or inducible aggregation of neurotoxic proteins in aging (Lim et al, 2020), the use of natural genetic variation to study resistance and resilience to protein aggregation in disease (Alexander-Floyd et al, 2020), the study of synergies between distinct pathological proteinopathies (Benbow et al, 2020;Latimer et al, 2022), the exploration of glia-neuron communication in protein quality control (Bar-Ziv et al, 2023), and the development of models to study prionlike seeding or spread of disease-causing proteins in neurons (Gallrein et al, 2021;Zanier et al, 2021). These approaches may inspire future ALS/FTLD models in C. elegans.…”