TFEB Transcriptional Responses Reveal Negative Feedback by BHLHE40 and BHLHE41

Kimberly L Carey; Geraldine L C Paulus; Lingfei Wang; Dale R Balce; Jessica W Luo; Phil Bergman; Ianina C Ferder; Lingjia Kong; Nicole Renaud; Shantanu Singh; Maria Kost-Alimova; Beat Nyfeler; Kara G Lassen; Herbert W Virgin; Ramnik J Xavier

doi:10.1016/j.celrep.2020.108371

TFEB Transcriptional Responses Reveal Negative Feedback by BHLHE40 and BHLHE41

Cell Rep. 2020 Nov 10;33(6):108371. doi: 10.1016/j.celrep.2020.108371.

Authors

Affiliations

¹ Immunology Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
³ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁴ Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
⁵ Imaging Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ Center for the Science of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Novartis Institutes for BioMedical Research, Basel, Switzerland.
⁸ Immunology Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁹ Immunology Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: xavier@molbio.mgh.harvard.edu.

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.

Keywords: BHLHE40; BHLHE41; TFEB; autophagy; gene regulation; lysosome; xenophagy.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism*
Cell Nucleus / genetics
Cell Nucleus / metabolism
Gene Knockout Techniques
HeLa Cells
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Humans
Lysosomes / metabolism
Mitochondria / metabolism
Transcription, Genetic

Substances

BHLHE40 protein, human
BHLHE41 protein, human
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Basic Helix-Loop-Helix Transcription Factors
Homeodomain Proteins
TFEB protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding