SUMOylation in development and neurodegeneration

Abstract

In essentially all eukaryotes, proteins can be modified by the attachment of small ubiquitin-related modifier (SUMO) proteins to lysine side chains to produce branched proteins. This process of 'SUMOylation' plays essential roles in plant and animal development by altering protein function in spatially and temporally controlled ways. In this Primer, we explain the process of SUMOylation and summarize how SUMOylation regulates a number of signal transduction pathways. Next, we discuss multiple roles of SUMOylation in the epigenetic control of transcription. In addition, we evaluate the role of SUMOylation in the etiology of neurodegenerative disorders, focusing on Parkinson's disease and cerebral ischemia. Finally, we discuss the possibility that SUMOylation may stimulate survival and neurogenesis of neuronal stem cells.

Keywords: Epigenetics; Neurodegenerative disorder; Post-translational protein modification; SUMO; Signal transduction; Ubiquitin-like protein.

Fig. 1.

The SUMOylation pathway and SUMO-interacting motifs. (A) (1) SUMO is cleaved to remove the entire C-terminal extension following the diglycine (GG) motif, by a SUMO-specific protease in the Ulp/SENP (Ulps) family, to generate mature SUMO. (2) Mature SUMO is attached to an active site cysteine residue in the SUMO-activating enzyme (a heterodimer of SAE1 and SAE2) in a process that requires ATP. (3) SUMO is transferred from the activating enzyme to a cysteine residue in UBC9, the SUMO-conjugating enzyme. (4) SUMO is transferred to a lysine side chain in a target protein. The target lysines are often embedded in a sequence resembling the four amino acid consensus sequence shown (ΨKXE, where Ψ is any hydrophobic amino acid and X is any amino acid). Target selection sometimes involves the action of an E3 SUMO ligase. (5) SUMOylation is a reversible process and its removal from target proteins is catalyzed by Ulp/SENP family SUMO proteases. (B) Many of the biological effects of SUMOylation are mediated by SUMO-interacting motifs (SIMs). These motifs generally consist of a short stretch of hydrophobic amino acids that bind to SUMO in a groove between a β-strand of the SUMO β-sheet and an α-helix. In doing so, the SIM forms a β-strand that adds to the SUMO β-sheet in either a parallel or an anti-parallel orientation. In the example shown here, the SIM from a PIAS family SUMO ligase, PIASx, interacts in parallel with the second SUMO β-strand (Song et al., 2004). The image was generated using PDB ID 2asq.

Fig. 2.

Regulation of signal transduction by SUMO. (A) Regulation of the Ras/MAPK pathway by SUMO. Upon ligand binding, a receptor tyrosine kinase dimerizes leading to auto-phosphorylation on tyrosine residues. Phosphorylation of the receptor activates a set of proteins that results in the phosphorylation of the downstream kinase MAPK. MAPK translocates into the cell nucleus to activate various transcription factors. This pathway is regulated by SUMO at multiple points. For example, in mammals SUMOylation of the adaptor protein GRB2 increases its affinity for the guanine nucleotide exchange factor SOS, and in Drosophila SUMOylation of PP2A may stimulate the removal of an inhibitory phosphate group from Raf. (B) Regulation of the Drosophila JNK pathway by Hipk and SUMOylation. When extracellular signals are sensed, a phosphorylation cascade results in phosphorylation of JNK proteins and their translocation into the nucleus to activate apoptotic genes through phosphorylation of transcription factors such as Jun. This process is enhanced by cytoplasmic Hipk; SUMOylation of Hipk results in its sequestration in the nucleus, thus reducing apoptosis. (C) Regulation of Drosophila Hedgehog signaling by SUMO. In the absence of Hedgehog signaling (left), the SUMO deconjugase Ulp1 binds Smo and removes SUMO from Smo preventing it from accumulating in a SUMOylated form. Smo protein is then subject to poly-ubiquitylation (Ub), which targets it to the proteasome for degradation. In the presence of Hedgehog signaling (right), Ulp1 dissociates from Smo, which therefore accumulates in a SUMOylated form. This leads to the recruitment of UBPY (also known as Usp8) through an interaction between its SIM and SUMO. UBPY is a deubiquitylase and therefore prevents accumulation of ubiquitylated Smo, thus preventing Smo degradation and allowing its accumulation on the cell surface.

Fig. 3.

Transcriptional gene silencing in Drosophila and Arabidopsis. (A) Polycomb group silencing and SUMO. Polycomb repressive complex 1 (PRC1) is recruited to Polycomb response elements (PREs) where it works with Scm to repress the transcription of Ubx. The SUMOylation of Scm impairs its recruitment to the PRE, and thus SUMOylation of Scm is required to allow Ubx expression under some conditions. (B) Transcriptional gene silencing and SUMOylation. In plants, AGO4 (in a complex with a siRNA shown in red), together with the aid of RDM1, recruits a DNA methylase (DRM2) to transcriptionally engaged RNA polymerase V (Pol V), which leads to RNA-dependent DNA methylation (RdRM) and transcriptional gene silencing (TGS). This silencing depends on the DNA damage response (DDR) chromatin-remodeling complex. SUMO appears to regulate this process, because mutations in the SUMO deconjugase OTS1 and the SUMO ligases SIZ1 and MMS21 compromise silencing. This suggests the existence of a SUMO-conjugated protein (Protein X) that promotes TGS when it is in its deconjugated form. M, cytosine methylation.