PARP14 is regulated by the PARP9/DTX3L complex and promotes interferon γ-induced ADP-ribosylation

Autor(es)

Ribeiro, Victoria Chaves ; Russo, Lilian Cristina ; Hoch, Nicolas Carlos

• Tipo de documento: Artigo Científico
• Fonte: EMBO Journal; v. 43, n. 14, p. 21-pg., 2024-06-04.

Resumo

Protein ADP-ribosylation plays important but ill-defined roles in antiviral signalling cascades such as the interferon response. Several viruses of clinical interest, including coronaviruses, express hydrolases that reverse ADP-ribosylation catalysed by host enzymes, suggesting an important role for this modification in host-pathogen interactions. However, which ADP-ribosyltransferases mediate host ADP-ribosylation, what proteins and pathways they target and how these modifications affect viral infection and pathogenesis is currently unclear. Here we show that host ADP-ribosyltransferase activity induced by IFN gamma signalling depends on PARP14 catalytic activity and that the PARP9/DTX3L complex is required to uphold PARP14 protein levels via post-translational mechanisms. Both the PARP9/DTX3L complex and PARP14 localise to IFN gamma-induced cytoplasmic inclusions containing ADP-ribosylated proteins, and both PARP14 itself and DTX3L are likely targets of PARP14 ADP-ribosylation. We provide evidence that these modifications are hydrolysed by the SARS-CoV-2 Nsp3 macrodomain, shedding light on the intricate cross-regulation between IFN-induced ADP-ribosyltransferases and the potential roles of the coronavirus macrodomain in counteracting their activity. Protein ADP-ribosylation plays important but ill-defined roles in antiviral signaling cascades. This study demonstrates that PARP9, DTX3L and PARP14 regulate IFN gamma-induced ADP-ribosylation, and explores an intricate cross-regulation between these factors proposed to be targets of the coronavirus macrodomain.PARP14 catalytic activity is required for IFN gamma-induced ADP-ribosylation. PARP9 and DTX3L regulate PARP14 protein stability. PARP9, DTX3L, PARP14 and ADPr co-localize in IFN gamma-induced cytoplasmic structures. IFN gamma induces PARP14-dependent modification of itself and of DTX3L, which may be hydrolyzed by the SARS-CoV2 macrodomain. Interferon signaling induces cytoplasmic colocalization and cross-regulation of two ADP-ribosyltransferases and a ubiquitin ligase. (AU)

• Processo FAPESP: 19/25914-1 - Função da ubiquitinação de histona H4 lisina 91 por PARP9/DTX3L na resposta celular a danos ao DNA
• Beneficiário: Victoria Chaves Ribeiro
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 15/02654-3 - EMU concedido no processo 2014/10492-0 microscópio de fluorescência
• Beneficiário: Alexandre Bruni Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Programa Equipamentos Multiusuários
• Processo FAPESP: 20/11162-5 - Desenvolvimento e aplicação de um ensaio celular para medir a atividade do macrodomínio de Nsp3 de SARS-CoV-2
• Beneficiário: Lilian Cristina Russo Vieira
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 19/06039-2 - EMU concedido no processo 2018/18007-5: microscópio TissueFAXS
• Beneficiário: Nicolas Carlos Hoch
• Modalidade de apoio: Auxílio à Pesquisa - Programa Equipamentos Multiusuários
• Processo FAPESP: 22/10947-4 - Apoio técnico avançado em técnicas de biologia celular e microscopia
• Beneficiário: Lilian Cristina Russo Vieira
• Modalidade de apoio: Bolsas no Brasil - Programa Capacitação - Treinamento Técnico
• Processo FAPESP: 18/18007-5 - ADP-ribosilação de proteínas: sinalização de danos ao DNA e impactos na saúde humana
• Beneficiário: Nicolas Carlos Hoch
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 23/15157-4 - Funções celulares do heterodímero PARP9/DTX3L
• Beneficiário: Victoria Chaves Ribeiro
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 20/05317-6 - Inibição do macrodomínio viral como estratégia de tratamento para Coronavírus
• Beneficiário: Nicolas Carlos Hoch
• Modalidade de apoio: Auxílio à Pesquisa - Regular