Neuralized-like protein 4 (NEURL4) mediates ADP-ribosylation of mitochondrial proteins

Author:

Cardamone Maria Dafne1ORCID,Gao Yuan1,Kwan Julian12,Hayashi Vanessa1ORCID,Sheeran Megan1ORCID,Xu Junxiang1ORCID,English Justin1ORCID,Orofino Joseph1ORCID,Emili Andrew12,Perissi Valentina1ORCID

Affiliation:

1. Department of Biochemistry, Boston University School of Medicine, Boston, MA

2. Center for Network Systems Biology, Boston University, Boston, MA

Abstract

ADP-ribosylation is a reversible post-translational modification where an ADP-ribose moiety is covalently attached to target proteins by ADP-ribosyltransferases (ARTs). Although best known for its nuclear roles, ADP-ribosylation is increasingly recognized as a key regulatory strategy across cellular compartments. ADP-ribosylation of mitochondrial proteins has been widely reported, but the exact nature of mitochondrial ART enzymes is debated. We have identified neuralized-like protein 4 (NEURL4) as a mitochondrial ART enzyme and show that most ART activity associated with mitochondria is lost in the absence of NEURL4. The NEURL4-dependent ADP-ribosylome in mitochondrial extracts from HeLa cells includes numerous mitochondrial proteins previously shown to be ADP-ribosylated. In particular, we show that NEURL4 is required for the regulation of mtDNA integrity via poly-ADP-ribosylation of mtLIG3, the rate-limiting enzyme for base excision repair (BER). Collectively, our studies reveal that NEURL4 acts as the main mitochondrial ART enzyme under physiological conditions and provide novel insights in the regulation of mitochondria homeostasis through ADP-ribosylation.

Funder

National Institutes of Health

Boston Nutrition and Obesity Center

Grunebaum Cancer Foundation

Publisher

Rockefeller University Press

Subject

Cell Biology

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