TY - JOUR
T1 - Neuralized-like protein 4 (NEURL4) mediates ADP-ribosylation of mitochondrial proteins
AU - Cardamone, Maria Dafne
AU - Gao, Yuan
AU - Kwan, Julian
AU - Hayashi, Vanessa
AU - Sheeran, Megan
AU - Xu, Junxiang
AU - English, Justin
AU - Orofino, Joseph
AU - Emili, Andrew
AU - Perissi, Valentina
N1 - Publisher Copyright:
© 2022, Cardamone et al. All rights reserved.
PY - 2022/3/7
Y1 - 2022/3/7
N2 - 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.
AB - 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.
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U2 - 10.1083/jcb.202101021
DO - 10.1083/jcb.202101021
M3 - Article
C2 - 35157000
AN - SCOPUS:85124592848
SN - 0021-9525
VL - 221
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 3
M1 - e202101021
ER -