Carey, Kimberly , Paulus, Geraldine , Wang, Lingfei , Balce, Dale , Bergman, Phil , Ferder, Ianina , Kong, Lingjia , Renaud, Nicole, Singh, Shantanu , Karhohs, Kyle, Carpenter, Anne, Kost-Alimova, Maria , Nyfeler, Beat, Lassen, Kara , Virgin, Herbert and Xavier, Ramnik (2020) TFEB Transcriptional Responses Reveal Negative Feedback by BHLHE40 and BHLHE41. Cell Reports, 33 (6). ISSN 22111247

Abstract

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.

Employing RNA sequencing, genome-wide CRISPR screening, and high-content subcellular imaging, Carey et al. systematically unravel localization- and stimulation-specific transcriptional responses to TFEB, including target gene activation at steady state. The authors further uncover a negative feedback loop by BHLHE40 and BHLHE41 that counteracts a TFEB transcriptional signature induced by lysosomal stress.

Item Type:	Article
Keywords:	autophagy BHLHE40 BHLHE41 gene regulation lysosome TFEB xenophagy
Date Deposited:	05 Oct 2021 00:45
Last Modified:	05 Oct 2021 00:45
URI:	https://oak.novartis.com/id/eprint/41436