TFEB Transcriptional Responses Reveal Negative Feedback by BHLHE40 and BHLHE41

• Autores: Carey, Kimberly L.; Paulus, Geraldine L. C.; Wang, Lingfei; Balce, Dale R.; Luo, Jessica W.; Bergman, Phil; Ferder, Ianina Claudia; Kong, Lingjia; Renaud, Nicole; Singh, Shantanu; Kost Alimova, Maria; Nyfeler, Beat; Lassen, Kara G.; Virgin, Herbert W.; Xavier, Ramnik J.
• Año de publicación: 2020
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: AUTOPHAGY; BHLHE40; BHLHE41; GENE REGULATION; LYSOSOME; TFEB; XENOPHAGY
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Transcription factor EB (TFEB) activates lysosomal biogenesis genes in response to environmental cues. Given implications of impaired TFEB signaling and lysosomal dysfunction in metabolic, neurological, and infectious diseases, we aim to systematically identify TFEB-directed circuits by examining transcriptional responses to TFEB subcellular localization and stimulation. We reveal that steady-state nuclear TFEB is sufficient to activate transcription of lysosomal, autophagy, and innate immunity genes, whereas other targets require higher thresholds of stimulation. Furthermore, we identify shared and distinct transcriptional signatures between mTOR inhibition and bacterial autophagy. Using a genome-wide CRISPR library, we find TFEB targets that protect cells from or sensitize cells to lysosomal cell death. BHLHE40 and BHLHE41, genes responsive to high, sustained levels of nuclear TFEB, act in opposition to TFEB upon lysosomal cell death induction. Further investigation identifies genes counter-regulated by TFEB and BHLHE40/41, adding this negative feedback to the current understanding of TFEB regulatory mechanisms.
Fil: Carey, Kimberly L.. Broad Institute of MIT and Harvard; Estados Unidos
Fil: Paulus, Geraldine L. C.. Harvard Medical School; Estados Unidos
Fil: Wang, Lingfei. Broad Institute of MIT and Harvard; Estados Unidos
Fil: Balce, Dale R.. Washington University in St. Louis; Estados Unidos
Fil: Luo, Jessica W.. Broad Institute of MIT and Harvard; Estados Unidos
Fil: Bergman, Phil. No especifíca;
Fil: Ferder, Ianina Claudia. Harvard Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Kong, Lingjia. Harvard Medical School; Estados Unidos
Fil: Renaud, Nicole. No especifíca;
Fil: Singh, Shantanu. Broad Institute of MIT and Harvard; Estados Unidos
Fil: Kost Alimova, Maria. Broad Institute of MIT and Harvard; Estados Unidos
Fil: Nyfeler, Beat. No especifíca;
Fil: Lassen, Kara G.. Harvard Medical School; Estados Unidos
Fil: Virgin, Herbert W.. Washington University in St. Louis; Estados Unidos
Fil: Xavier, Ramnik J.. Harvard Medical School; Estados Unidos