2016
DOI: 10.1126/science.aad6872
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Abstract: Inhibition or genetic deletion of poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) is protective against toxic insults in many organ systems. The molecular mechanisms underlying PARP-1–dependent cell death involve release of mitochondrial apoptosis-inducing factor (AIF) and its translocation to the nucleus, which results in chromatinolysis. We identified macrophage migration inhibitory factor (MIF) as a PARP-1–dependent AIF-associated nuclease (PAAN). AIF was required for recruitment of MIF to the nucleus, where M… Show more

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Cited by 270 publications
(232 citation statements)
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“…In contrast, cell death regulator heat-shock protein 70 (Hsp70) (Schmitt et al., 2003) and E3-ubiquitin ligase X-linked inhibitor of apoptosis protein (XIAP) (Lewis et al, 2011) target residues near AIF’s Cβ-clasp (K192, K194) and dimerization interface (K255), respectively, suggesting a requirement for the closed, monomeric architecture of oxidized AIF. The recent discovery of added mitochondrial binding partners of AIF (Lenhausen et al, 2016; Nakao et al, 2015) and a PARP-1-dependent AIF-associated nuclease (Wang et al., 2016) opens further opportunities for finding how the mechanism for architectural switching defined here regulates AIF’s mitochondrial and cell death functions in vivo .…”
Section: Discussionmentioning
confidence: 99%
“…In contrast, cell death regulator heat-shock protein 70 (Hsp70) (Schmitt et al., 2003) and E3-ubiquitin ligase X-linked inhibitor of apoptosis protein (XIAP) (Lewis et al, 2011) target residues near AIF’s Cβ-clasp (K192, K194) and dimerization interface (K255), respectively, suggesting a requirement for the closed, monomeric architecture of oxidized AIF. The recent discovery of added mitochondrial binding partners of AIF (Lenhausen et al, 2016; Nakao et al, 2015) and a PARP-1-dependent AIF-associated nuclease (Wang et al., 2016) opens further opportunities for finding how the mechanism for architectural switching defined here regulates AIF’s mitochondrial and cell death functions in vivo .…”
Section: Discussionmentioning
confidence: 99%
“…Exposure to N-methyl-N-nitro-N-nitrosoguanidine (MNNG), a DNA-alkylating agent, leads to extensive activation of PARP-1, which triggers the release of apoptosis-inducing factor (AIF) from mitochondria (Yu et al 2002). AIF then translocates into the nucleus, where it recruits the nuclease MIF (macrophage migration inhibitory factor), which cleaves genomic DNA into large fragments, resulting in chromatinolysis (Wang et al 2016). Thus, the level of PARP-1 activation can serve as a rheostat: As the strength of the stress stimulus increases, the levels of PARP-1 activity and PAR synthesis increase, leading to different cellular outcomes (i.e., inflammatory responses, DNA repair and cell survival, senescence, or cell death [e.g., apoptosis, necrosis, and parthanatos]) (Luo and Kraus 2012).…”
Section: Nad + Consumersmentioning
confidence: 99%
“…Overactivation of PARP1 leads to increased PAR levels, which act as a signal from the nucleus to the mitochondria where PAR binds to Apoptosis Inducing Factor-1 (AIF), resulting in its translocation from the mitochondria to the nucleus. AIF interacts with macrophage migration inhibitory factor (MIF) where it recruits MIF to the nuclease (Wang et al, 2016). Once inside the nucleus MIF’s nuclease activity leads to extensive DNA fragmentation and caspase-independent cell death (Wang et al, 2016).…”
Section: Common Pathways In Pd Pathogenesismentioning
confidence: 99%
“…AIF interacts with macrophage migration inhibitory factor (MIF) where it recruits MIF to the nuclease (Wang et al, 2016). Once inside the nucleus MIF’s nuclease activity leads to extensive DNA fragmentation and caspase-independent cell death (Wang et al, 2016). These data establish a direct link between parkin and the cell death pathway called parthanatos, leading to DA neurodegeneration.…”
Section: Common Pathways In Pd Pathogenesismentioning
confidence: 99%