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

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.

ADP-ribosylation from molecular mechanisms to therapeutic implications

“… 36 The PARP-like protein NEURL4 has recently been reported to function in the mitochondria. 37 This complex picture, which is likely far from comprehensive, hints at different PARPs occupying diverse, partially overlapping, spatial niches. This might in turn reflect functional compartmentalization, although there might also be functional crosstalk between different PARPs, especially when they are situated in the same locations.…”

ADP-Ribosylation Post-Translational Modification: An Overview with a Focus on RNA Biology and New Pharmacological Perspectives

“…Reversible ADPr reaction regulates a plethora of fundamental biological processes in mammals, as diverse as DDR [26,[122][123][124][125][126], transcription, cell division [62,64,127], cell proliferation [128][129][130], cell death [131][132][133][134] immune and stress responses [76,77], as well as other emerging pathways [78,135,136]. For further details on the functional outcomes modulated by ADPr, we refer the reader to the valuable and specialized reviews in the field [24,26,[137][138][139][140][141][142].…”

The DarT/DarG Toxin–Antitoxin ADP-Ribosylation System as a Novel Target for a Rational Design of Innovative Antimicrobial Strategies

“…Today, it is mainly known in the scientific community for its key role in DNA damage repair [ 7 , 8 , 9 , 10 ] and for being the target of tailored cancer therapies [ 11 , 12 , 13 , 14 ]. However, the functions of ADP-ribosylation are also vital for controlling many additional physiological processes, such as transcription and translation [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ], cell proliferation [ 22 , 23 ], and cell death [ 24 , 25 , 26 ] along with stress and immune responses [ 27 , 28 , 29 , 30 , 31 , 32 , 33 ] and many others [ 34 , 35 , 36 ]. The control of cell homeostasis in both prokaryotes and eukaryotes by ADP-ribosylation [ 19 , 34 , 35 , 37 , 38 , 39 , 40 , 41 ] makes this a PTM of great interest in many fields of human health.…”