Targeting the PIAS1 SUMO ligase pathway to control inflammation

Abstract

Protein sumoylation is a post-translational-modification event, in which small ubiquitin-like modifier (SUMO) is covalently attached to protein substrates by a three-step process. Sumoylation has been suggested to regulate multiple cellular processes, including inflammation. Inflammation is initiated in response to pathogenic infections, but uncontrolled inflammatory responses can lead to the development of inflammatory disorders such as rheumatoid arthritis. Recent studies indicate that proinflammatory stimuli, such as tumor necrosis factor alpha and lipopolysaccharide, can activate PIAS1 [protein inhibitor of activated STAT1 (signal transducer and activator of transcription 1)] SUMO E3 ligase through a SUMO-dependent, inhibitor of kappaB kinase alpha (IKKalpha)-mediated phosphorylation event. Activated PIAS1 is then recruited to inflammatory gene promoters to repress transcription. These findings support a hypothesis that therapies targeting the PIAS1 SUMO ligase pathway might be developed for the treatment of inflammatory disorders such as rheumatoid arthritis and atherosclerosis.

Figure 1

Regulation of PIAS1-mediated transcriptional repression by phosphorylation and sumoylation. (a) PIAS1 directly binds to chromatin and represses NF-κB-mediated transcription in response to inflammatory stimuli, which is regulated by ligand-induced Ser90 phosphorylation of PIAS1. The IKKα kinase is activated by inflammatory stimuli such as TNF and LPS, which then translocates into the nucleus where it interacts with PIAS1 and phosphorylates PIAS1 at Ser90. The IKKα-mediated PIAS1 phosphorylation is dependent on the SUMO E3 ligase activity of PIAS1, indicating that the possible sumoylation (represented as ‘Su?’) of PIAS1 and/or IKKα might be involved in this process. Phosphorylated PIAS1 disassociates from IKKα and then binds to the promoters of PIAS1-regulated genes for transcriptional repression. (b) PIAS1 also participates in PPARγ-mediated transrepression by acting as SUMO E3 ligase for PPARγ. In response to a PPARγ agonist, such as rosiglitazone (Ro), PPARγ is activated via PIAS1-mediated sumoylation and recruited to the NCoR–HDAC3 corepressor complex, preventing the degradation of the NCoR–HDAC3 complex by the ubiquitin–proteosome pathway and resulting in transrepression. Abbreviation: Ub, ubiquitylation.

Figure 2

The proposed mechanisms of PIAS1 specificity in gene regulation. In response to signals, PIAS1 selectively represses the induction of a subset of genes (PIAS1- sensitive genes) by blocking the DNA-binding activity of transcription factors (TFs), such as STAT1 and NF-κB. For genes that are not regulated by PIAS1 (PIAS1-insensitive genes), three possible mechanisms might contribute. (a) The promoters of these genes do not contain sequence-specific binding site(s) for PIAS1 (red box). (b) The TF has a high affinity for the gene promoters that cannot be inhibited by PIAS1. (c) Genes might be regulated by PIAS family members, such as PIAS1 and PIASy. In the absence of PIAS1, PIASy can still inhibit gene transcription.

Figure 1

The SUMO conjugation pathway. Sumoylation involves three discrete steps, activation, conjugation and ligation, which are mediated by E1, E2 and E3, respectively. SUMO modification is reversible. In the mammalian system, SUMO-specific proteases (SENPs) proteolytically remove SUMO from protein substrates.

Figure 1

PIAS1-mediated repression of STAT1 and NF-κB pathways. (a) The domain structure of PIAS proteins. (b) Upon ligand stimulation, STAT1 and NF-κB translocate into the nucleus, via distinct mechanisms, where they bind to gene promoters and activate transcription. PIAS1 blocks the DNA-binding activity of STAT1 and NF-κB, resulting in transcriptional repression. Abbreviations: P, phosphorylation; SH2–PY, interaction between the SH2 domain and phosphorylated Tyr701; Ub, ubiquitylation.