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    • Within the PARP family TIPARP

    2024-02-01

    Within the PARP family, TIPARP is most evolutionarily conserved with PARP12 (ARTD12) and PARP13 (ARTD13) [27,28,41]. All three proteins contain at least one RNA-type CCCH zinc finger domain, a poly-ADP-ribose binding WWE domain and a PARP catalytic domain (Fig. 1). PARP13 is catalytically inactive, but has a role in antiviral defence by specifically binding to retroviral RNA through its zinc finger domains [42]. TIPARP and PARP12 also inhibit viral replication; however, the mechanism is unknown [40,43]. In addition, TIPARP has been implicated in the maintenance of embryonic stem cell pluripotency and in mitosis, suggesting that it has an important role in development and cell differentiation [41,44]. Tiparp null mice are viable, but are born at sub-mendelian birth ratios and with numerous phenotypes, including vascular defects such as hemorrhaging and microaneurisms [45,46]. Tiparp null females are infertile and have enlarged polycystic ovaries, which is of interest since TIPARP is associated with increased risk for ovarian cancer [46,47].
    The AHR-TIPARP negative feedback axis Studies using human TIPARP show that it is recruited to AHR target prostaglandin synthase in a TCDD-dependent manner and functions as a negative regulator of AHR activity [27,48]. Overexpression of either human or mouse TIPARP reduces, while their knockdown or knockout increases AHR-mediated transcription prostaglandin synthase through a mechanism involving reduced AHR protein levels [27]. TIPARP catalytic activity and an intact zinc finger domain are required to repress AHR. Consistent with these findings, TIPARP selectively ADP-ribosylates AHR, but not ARNT, while MACROD1 reverses the repressive effects of TIPARP [48]. These results reveal previously unidentified roles for TIPARP, MACROD1, and ADP-ribosylation in transcriptional regulation of AHR and show that TIPARP is part of a negative feedback loop regulating AHR activity and some of its downstream target genes (Fig. 2) [48,49]. TIPARP's regulation of AHR protein levels, suggests that it may be a more general negative regulator of AHR compared with AHRR [50]. AHR is regulated by several posttranslational modifications, including phosphorylation, sulfonation, ubiquitination and SUMOylation [38,51,52]. ADP-ribosylation can be added to this list, but exactly how ADP-ribosylation affects AHR activity and more importantly, which residues are modified have not been determined. ADP-ribosylation occurs on many different amino acid residues (arginine, lysine, cysteine and acidic residues), but no consensus sequence has been identified [53]. Poly-ADP-ribosylation serves as a signal for polyubiquitination and degradation of several crucial regulatory proteins [54], so it is possible that mono-ADP-ribosylation modulates the ubiquitination status of AHR. The different posttranslational modifications of AHR may influence the recruitment and composition of coactivator/corepressor complexes leading to altered regulation of known AHR target genes. Alternatively, TIPARP ADP-ribosylation of core histones may alter AHR activity at selectively modified target genes [11,27].
    TIPARP protects against TCDD toxicity and wasting syndrome Consistent with in vitro data, Tiparp deficient mice exhibit increased AHR responsiveness and increased sensitivity to TCDD-induced wasting syndrome [48]. Male Tiparp deficient mice given a single intraperitoneal injection of 10 or 100 μg/kg/bw TCDD do not survive beyond day 8 and day 3, respectively; all wildtype mice survived the 30 day treatment [48]. The lethal dose 50 (LD50) for wildtype C57BL/6 mice ranges from 200 to 500 μg/kg and a dose of 10 μg/kg is not lethal in any mouse strain [17]. In Tiparp deficient mice high dose TCDD (100 μg/kg/bw) causes a greater than 20% loss in body weight in 3 days, which is in part caused by hypophagia. Lethality, however, is not overcome by fluid, electrolyte and glucose supplementation [48]. Treated Tiparp deficient mice also show increased hepatosteatosis, infiltration of immune cells and hepatotoxicity compared with wildtype. The increased hepatic lipid levels are due to increased uptake rather than de novo lipogenesis [20,48]. Well-defined TCDD-induced toxic endpoints, including thymic atrophy, increased liver weight, and reduced phosphoenolpyruvate carboxykinase 1 (PCK1) mRNA levels are unaffected, showing that not all TCDD-dependent toxic outcomes are affected by loss of Tiparp. Taken together, these findings show that under normal conditions TIPARP via ADP-ribosylation regulates AHR activity and protects against TCDD-dependent toxicities including wasting syndrome. In the absence of TIPARP, AHR activity is enhanced which in turn increases sensitivity to the toxic effects of TCDD (Fig. 3).