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Review
. 2008 Jun;20(3):288-93.
doi: 10.1016/j.ceb.2008.03.014. Epub 2008 May 28.

Regulation of the sumoylation system in gene expression

Bin Liu  1 , Ke Shuai
Affiliations
Review

Regulation of the sumoylation system in gene expression

Bin Liu et al. Curr Opin Cell Biol. 2008 Jun.

Abstract

Protein sumoylation has emerged as an important regulatory mechanism for the transcriptional machinery. Sumoylation is a highly dynamic process that is regulated in response to cellular stimuli or pathogenic challenges. Altered activity of the small ubiquitin-like modifier (SUMO) conjugation system is associated with human cancers and inflammation. Thus, understanding the regulation of protein sumoylation is important for the design of SUMO-based therapeutic strategies for the treatment of human diseases. Recent studies indicate that the sumoylation system can be regulated through multiple mechanisms, including the regulation of the expression of various components of the sumoylation pathway, and the modulation of the activity of SUMO enzymes. In addition, extracellular stimuli can signal the nucleus to trigger the rapid promoter recruitment of SUMO E3 ligases, resulting in the immediate repression of transcription. Finally, the sumoylation system can also be regulated through crosstalk with other post-translational modifications, including phosphorylation, ubiquitination, and acetylation.

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Figures

Figure 1
Figure 1. The regulation of the SUMOylation system
A schematic representation of the regulation of the SUMO conjugation system at multiple steps. Protein sumoylation is accomplished in three steps involving three groups of enzymes: E1 (SAE1/SAE2), E2 (UBC9), and E3 ligases such as protein inhibitors of activated STAT (PIAS), Ran binding protein 2 (RanBP2), and the polycomb group protein Pc2. The SUMO-specific protease (SENP) family is responsible for the removal of SUMO from substrates. Hypoxia can induce the expression of SUMO-1 and an RWD-containing sumoylation enhancer (RSUME). Viral proteins such as Gam1 can target SAE1 for degradation through the ubiquitin-proteasome pathway. DNA damage can induce the SUMO ligase activity of Pc2. Cytokines such as TNFα signal to the nucleus to target PIAS1 E3 ligase for gene repression (See Figure 2 for details). Reactive oxygen species (ROS) can cause the formation of UBC9-SAE2 complex, which inhibits UBC9-SUMO thioester formation. RSUME binds to UBC9 to promote UBC9-SUMO thioester formation.
Figure 2
Figure 2. A signaling pathway to recruit PIAS1 SUMO E3 ligase to gene promoters for transcriptional repression
Inflammatory stimuli such as TNFα and LPS activates the kinase IKKα, which then translocates into the nucleus where it binds to PIAS1 and then phosphorylates PIAS1 on Ser90 residue. The IKKα-mediated PIAS1 phosphorylation is dependent on the SUMO E3 ligase activity of PIAS1, suggesting the possible sumoylation (Su?) of PIAS1 and/or IKKα during this process. Phosphorylated PIAS1 disassociates from IKKα, and is then recruited to the promoters of PIAS1-responsive genes for transcriptional repression.
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