JAK/STAT signaling and ARTD family members (WP5528)

Homo sapiens

Both PARP9 (ARTD9) and PARP14 are highly expressed and undergo increased ADP-ribosylation in IFNγ-stimulated THP-1 cells. Notably, PARP9 and PARP14 have opposing roles in macrophages, with PARP9 promoting anti-inflammatory effects and PARP14 enhancing proinflammatory responses, thus regulating macrophage activation. Additionally, the expression of PARP9 is controlled by the IFNγ-JAK2/STAT1-IRF1 signaling pathway, which is essential for the survival of cancer cells in diffuse large B-cell lymphoma (DLBCL) with an active host inflammatory response. Positive regulation In macrophages, the phosphorylation of STAT6 induced by IL-4 and the subsequent activation of anti-inflammatory genes depend on the activation of PARP14, which likely involves PARP14-mediated ADP-ribosylation of STAT6. The role of PARP14 in the ADP-ribosylation of STAT6 for gene activation presents a potential therapeutic target to mitigate the progression of allergic airway diseases. PARP1 positively influences STAT6-dependent transcriptional activation. Reduced PARP1 levels lead to decreased STAT6 protein stability, resulting in lowered IL-5 expression in murine splenocytes. Moreover, excessive activation of PARP1, causing NAD+ depletion, is believed to contribute to the development of various cardiovascular diseases, such as atherosclerosis and cardiac hypertrophy. In a phenylephrine-induced cardiac hypertrophy model, PARP1 and its enzymatic activity help retain phosphorylated STAT3 in the nucleus, extending its transcriptional activity independent of JAK2, which contributes to the hypertrophy phenotype. PARP9, in association with its binding partner DTX3L, is involved in STAT1-mediated interferon signaling. The PARP9/DTX3L complex is a key factor regulating STAT1 transcriptional activity and enhances the host defense response following viral infection. In DLBCL, PARP9 stimulates the phosphorylation of both STAT1 isoforms, particularly promoting the nuclear accumulation of the transcriptionally repressive STAT1β isoform. PARP9, together with STAT1β, inhibits the expression of the tumor suppressor IRF1, while enhancing the expression of proto-oncogenes such as IRF2 and BCL6. In this context, PARP9 suppresses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-p53 pathway, thereby promoting cell proliferation and survival in DLBCL. Negative regulation Viral infection triggers the expression of PARP11 (ARTD11), which mono-ADP-ribosylates the E3 ubiquitin ligase β-TrCP. This modification leads to the ubiquitination and degradation of IFNAR1, ultimately suppressing the IFN antiviral signaling pathway. In response to influenza A viral infection, PARP1 transiently co-localizes with HA in the cytoplasm, mediating the degradation of IFNAR1 in an ADP-ribosylation-dependent manner. In ovarian, lung, and colon cancer cell lines, PARP1 downregulates PD-L1 expression by ADP-ribosylating STAT3, which decreases its phosphorylation. This contrasts with the positive regulation of STAT3 described earlier, highlighting the context-dependent regulation of STAT3 by PARP1.

Authors

Eric Weitz

Activity

last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.

Organisms

Homo sapiens

Communities

Annotations

Disease Ontology

colon cancer lung cancer ovarian cancer diffuse large B-cell lymphoma

Cell Type Ontology

splenocyte macrophage

Pathway Ontology

Jak-Stat signaling pathway

Participants

Label Type Compact URI Comment
Hemagglutinin GeneProduct interpro:PF00509 'HA' originally
STAT1 GeneProduct ensembl:ENSG00000115415
STAT3 GeneProduct ensembl:ENSG00000168610
STAT6 GeneProduct ensembl:ENSG00000166888
HDAC2 GeneProduct ensembl:ENSG00000196591
DTX3L GeneProduct ensembl:ENSG00000163840
HDAC3 GeneProduct ensembl:ENSG00000171720
RBX1 GeneProduct ensembl:ENSG00000100387
SKP1 GeneProduct ensembl:ENSG00000113558
CUL1 GeneProduct ensembl:ENSG00000055130
BTRC GeneProduct ensembl:ENSG00000166167
PARP14 GeneProduct ensembl:ENSG00000173193
PARP1 GeneProduct ensembl:ENSG00000143799
PARP11 GeneProduct ensembl:ENSG00000111224
PARP9 GeneProduct ensembl:ENSG00000138496

References

  1. Interplay between ADP-ribosyltransferases and essential cell signaling pathways controls cellular responses. Boehi F, Manetsch P, Hottiger MO. Cell Discov. 2021 Nov 2;7(1):104. PubMed Europe PMC Scholia