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1.
Int J Mol Sci ; 23(14)2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35887176

RESUMO

Parthanatos is programmed cell death mediated by poly(ADP-ribose) polymerase 1 (PARP1) after DNA damage. PARP1 acts by catalyzing the transfer of poly(ADP-ribose) (PAR) polymers to various nuclear proteins. PAR is subsequently cleaved, generating protein-free PAR polymers, which are translocated to the cytoplasm where they associate with cytoplasmic and mitochondrial proteins, altering their functions and leading to cell death. Proteomic studies revealed that several proteins involved in endocytosis bind PAR after PARP1 activation, suggesting endocytosis may be affected by the parthanatos process. Endocytosis is a mechanism for cellular uptake of membrane-impermeant nutrients. Rab5, a small G-protein, is associated with the plasma membrane and early endosomes. Once activated by binding GTP, Rab5 recruits its effectors to early endosomes and regulates their fusion. Here, we report that after DNA damage, PARP1-generated PAR binds to Rab5, suppressing its activity. As a result, Rab5 is dissociated from endosomal vesicles, inhibiting the uptake of membrane-impermeant nutrients. This PARP1-dependent inhibition of nutrient uptake leads to cell starvation and death. It thus appears that this mechanism may represent a novel parthanatos pathway.


Assuntos
Parthanatos , Proteômica , Dano ao DNA , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli Adenosina Difosfato Ribose/metabolismo , Polímeros
2.
Genes Cells ; 27(4): 305-312, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35124853

RESUMO

Mono(ADP-ribosyl)ation and poly(ADP-ribosyl)ation are posttranslational modifications evolutionarily conserved in prokaryotes and eukaryotes. They entail transfer of one or more ADP-ribose moieties from NAD+ to acceptor proteins with the simultaneous release of nicotinamide. The resultant ADP-ribosylated acceptor proteins regulate diverse cellular functions. For instance, ADP-ribosyltransferase 1 (ART1) catalyzes mono(ADP-ribosyl)ation of arginine residues in Trim72, a protein specifically expressed in muscle cells and involved in cell membrane repair, which is enhanced upon its ADP-ribosylation. By contrast, the contribution made by ADP-ribosylation to membrane repair in epithelial cells remains unclear. In this study, we investigated the involvement of ADP-ribosylation in cell membrane repair in HEK293T and HeLa cells. We found that upon induction of membrane damage using streptolysin-O, poly(ADP-ribose) polymerase 1 (PARP1) catalyzed poly(ADP-ribosyl)ation. In scratch assays, inhibition of PARP1 activity using the nonspecific PARP inhibitor PJ34 or shRNA targeting PARP1 delayed wound healing, suggesting that PARP1-catalyzed poly(ADP-ribosyl)ation plays a key role in membrane repair in epithelial cells.


Assuntos
Poli(ADP-Ribose) Polimerase-1 , Poli ADP Ribosilação , Poli Adenosina Difosfato Ribose , Células HEK293 , Células HeLa , Humanos , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli Adenosina Difosfato Ribose/metabolismo , Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo
3.
J Biol Chem ; 296: 100046, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33168626

RESUMO

Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear protein that is activated by binding to DNA lesions and catalyzes poly(ADP-ribosyl)ation of nuclear acceptor proteins, including PARP1 itself, to recruit DNA repair machinery to DNA lesions. When excessive DNA damage occurs, poly(ADP-ribose) (PAR) produced by PARP1 is translocated to the cytoplasm, changing the activity and localization of cytoplasmic proteins, e.g., apoptosis-inducing factor (AIF), hexokinase, and resulting in cell death. This cascade, termed parthanatos, is a caspase-independent programmed cell death distinct from necrosis and apoptosis. In contrast, PARP1 is a substrate of activated caspases 3 and 7 in caspase-dependent apoptosis. Once cleaved, PARP1 loses its activity, thereby suppressing DNA repair. Caspase cleavage of PARP1 occurs within a nuclear localization signal near the DNA-binding domain, resulting in the formation of 24-kDa and 89-kDa fragments. In the present study, we found that caspase activation by staurosporine- and actinomycin D-induced PARP1 autopoly(ADP-ribosyl)ation and fragmentation, generating poly(ADP-ribosyl)ated 89-kDa and 24-kDa PARP1 fragments. The 89-kDa PARP1 fragments with covalently attached PAR polymers were translocated to the cytoplasm, whereas 24-kDa fragments remained associated with DNA lesions. In the cytoplasm, AIF binding to PAR attached to the 89-kDa PARP1 fragment facilitated its translocation to the nucleus. Thus, the 89-kDa PARP1 fragment is a PAR carrier to the cytoplasm, inducing AIF release from mitochondria. Elucidation of the caspase-mediated interaction between apoptosis and parthanatos pathways extend the current knowledge on mechanisms underlying programmed cell death and may lead to new therapeutic targets.


Assuntos
Fator de Indução de Apoptose/metabolismo , Apoptose , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli Adenosina Difosfato Ribose/metabolismo , Proteólise , Fator de Indução de Apoptose/genética , Transporte Biológico Ativo , Caspase 3/genética , Caspase 3/metabolismo , Caspase 7/genética , Caspase 7/metabolismo , Citoplasma/genética , Citoplasma/metabolismo , Células HeLa , Humanos , Poli(ADP-Ribose) Polimerase-1/genética , Poli Adenosina Difosfato Ribose/genética
4.
Biol Pharm Bull ; 41(10): 1611-1614, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30270332

RESUMO

Lymphocytic cholinergic system has important roles in T cell functions, including immune responses and proliferation and differentiation of immune cells. T lymphocytes exclusively produces acetylcholine (ACh) via choline acetyltransferase (ChAT), activating their muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively) in an autocrine and paracrine manners. Hippocampal cholinergic neurostimulating peptide (HCNP) is an undecapeptide cleaved from N-terminal of phosphatidylethanolamine-binding protein 1 (PEBP1). HCNP enhances ACh synthesis through upreglation of ChAT expression in septo-hippocampal cholinergic neurons and participates in neuronal development and differentiation. Although PEBP1 and HCNP appears to be distributed ubiquitously in tissues and cells including spleen, its functions in immune cells have not been understood. In the present study, we observed that PEBP1 is also expressed in human and murine T cells. Long-term exposure to HCNP suppressed ChAT expression in MOLT3 human leukemic T cells, resulting in decreased release of ACh. HCNP also decreased the expression of extracellular signal-regulated kinase (ERK). Thus, HCNP appears to suppress lymphocytic cholinergic signaling, which might act as an immune modulator.


Assuntos
Acetilcolina/biossíntese , Colina O-Acetiltransferase/metabolismo , Neuropeptídeos/metabolismo , Linfócitos T/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Neurônios Colinérgicos/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hipocampo/metabolismo , Humanos , Imunidade , Camundongos , Proteína de Ligação a Fosfatidiletanolamina/metabolismo
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