A Cellular Mechanism to Detect and Alleviate Reductive Stress

Andrew G Manford; Fernando Rodríguez-Pérez; Karen Y Shih; Zhuo Shi; Charles A Berdan; Mangyu Choe; Denis V Titov; Daniel K Nomura; Michael Rape

doi:10.1016/j.cell.2020.08.034

A Cellular Mechanism to Detect and Alleviate Reductive Stress

Cell. 2020 Oct 1;183(1):46-61.e21. doi: 10.1016/j.cell.2020.08.034. Epub 2020 Sep 16.

Authors

Andrew G Manford¹, Fernando Rodríguez-Pérez², Karen Y Shih², Zhuo Shi¹, Charles A Berdan³, Mangyu Choe⁴, Denis V Titov⁴, Daniel K Nomura⁵, Michael Rape⁶

Affiliations

¹ Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley CA 94720, USA.
² Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley CA 94720, USA; Howard Hughes Medical Institute, University of California at Berkeley, Berkeley CA 94720, USA.
³ Department of Nutritional Science and Toxicology, University of California at Berkeley, Berkeley CA 94720, USA.
⁴ Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley CA 94720, USA; Department of Nutritional Science and Toxicology, University of California at Berkeley, Berkeley CA 94720, USA; Center for Computational Biology, University of California at Berkeley, Berkeley CA 94720, USA.
⁵ Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley CA 94720, USA; Department of Nutritional Science and Toxicology, University of California at Berkeley, Berkeley CA 94720, USA; Department of Chemistry, University of California at Berkeley, CA 94720, USA.
⁶ Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley CA 94720, USA; Howard Hughes Medical Institute, University of California at Berkeley, Berkeley CA 94720, USA; California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, CA 94720, USA. Electronic address: mrape@berkeley.edu.

PMID: 32941802
DOI: 10.1016/j.cell.2020.08.034

Abstract

Metazoan organisms rely on conserved stress response pathways to alleviate adverse conditions and preserve cellular integrity. Stress responses are particularly important in stem cells that provide lifetime support for tissue formation and repair, but how these protective systems are integrated into developmental programs is poorly understood. Here we used myoblast differentiation to identify the E3 ligase CUL2^FEM1B and its substrate FNIP1 as core components of the reductive stress response. Reductive stress, as caused by prolonged antioxidant signaling or mitochondrial inactivity, reverts the oxidation of invariant Cys residues in FNIP1 and allows CUL2^FEM1B to recognize its target. The ensuing proteasomal degradation of FNIP1 restores mitochondrial activity to preserve redox homeostasis and stem cell integrity. The reductive stress response is therefore built around a ubiquitin-dependent rheostat that tunes mitochondrial activity to redox needs and implicates metabolic control in coordination of stress and developmental signaling.

Keywords: FEM1B; FNIP1; KEAP1; mitochondria; oxidative stress; proteasome; reactive oxygen; reductive stress; ubiquitin.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antioxidants / metabolism
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Cell Differentiation
HEK293 Cells
Homeostasis
Humans
Kelch-Like ECH-Associated Protein 1 / metabolism
Mitochondria
Muscle Development / physiology
Myoblasts / metabolism
NF-E2-Related Factor 2 / metabolism
Oxidative Stress / physiology*
Reactive Oxygen Species / metabolism*
Signal Transduction
Ubiquitin-Protein Ligases / metabolism
Ubiquitination

Substances

Antioxidants
Carrier Proteins
FNIP1 protein, human
Kelch-Like ECH-Associated Protein 1
NF-E2-Related Factor 2
Reactive Oxygen Species
Ubiquitin-Protein Ligases

Abstract

Publication types

MeSH terms

Substances

Grants and funding