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Chordate PIAS proteins act as conserved repressors of the TRAF6 self-polyubiquitination
- Source :
- Developmental and comparative immunology. 104
- Publication Year :
- 2019
-
Abstract
- In mammals, PIAS proteins are important SUMO E3 ligases and act as versatile regulators of over sixty different proteins, including components from the NF-κB pathways. But the PIAS functions are not well-understood due to complicated molecular mechanisms and multiple gene paralogs with overlapping roles, which is especially true in lower vertebrates where dedicated studies are scarce. As a basal chordate with a single PIAS gene, amphioxus is a convenient model to study PIAS from the evolutionary perspective. TRAF6 is a critical adaptor of the NF-κB pathways but it is not known whether TRAF6 is regulated by PIAS. Here we discover that in mammalian cells, amphioxus PIAS inhibited NF-κB activation by co-localizing and binding with TRAF6. The interaction relied on the N-terminal SAP and PINIT domains of PIAS. TRAF6 is an E3 ubiquitin ligase, which initiates downstream NF-κB signaling by promoting its self-ubiquitination. Both amphioxus SUMO1 and Ubc9 (SUMO E2 ligase) could suppress TRAF6 self-ubiquitination and NF-κB activation, suggesting that the SUMOylation activity competed away the ubiquitination activity of TRAF6. However, we show that the wild-type PIAS and the mutant PIAS without SUMO E3 ligase activity both could inhibit TRAF6-mediated NF-κB activation by reducing TRAF6 self-ubiquitination. This implies that SUMO ligase activity is not the only mechanism for PIAS to negatively regulate TRAF6. Finally, we tested the interactions between human PIAS1-4 and TRAF6. It reveals that human PIAS1, 3 and 4, but not 2, were able to repress NF-κB activation by reducing TRAF6 self-ubiquitination. Taken together, our study discovers a conserved regulatory interaction between chordate PIAS and TRAF6. It therefore sheds light on the complicated role of PIAS in immune regulation, and may help to understand the PIAS functions in other lower chordate taxa, such as jawless and jawed fishes.
- Subjects :
- 0301 basic medicine
SUMO ligase activity
Immunology
Mutant
SUMO protein
Repressor
Chordate
03 medical and health sciences
0302 clinical medicine
Ubiquitin
Animals
Chordata
Polyubiquitin
Conserved Sequence
Lancelets
chemistry.chemical_classification
TNF Receptor-Associated Factor 6
DNA ligase
biology
NF-kappa B
Ubiquitination
biology.organism_classification
Protein Inhibitors of Activated STAT
Cell biology
Ubiquitin ligase
Repressor Proteins
030104 developmental biology
chemistry
030220 oncology & carcinogenesis
biology.protein
Small Ubiquitin-Related Modifier Proteins
Developmental Biology
Signal Transduction
Subjects
Details
- ISSN :
- 18790089
- Volume :
- 104
- Database :
- OpenAIRE
- Journal :
- Developmental and comparative immunology
- Accession number :
- edsair.doi.dedup.....c616983ce624c193caf9e159c66a6af7