Mechanistic and functional aspects of SUMO-SIM interactions

Signaling by SUMO relies on the recognition of the post-translational mark by specialized interaction modules termed SUMO interaction motifs (SIMs). SUMO-mediated protein/protein interactions are frequently mediated by the non-covalent binding of SUMO conjugates to SIMs in a binding partner.
A common key determinant of SIMs is a core of hydrophobic amino acids. In a subset of SIM-containing proteins, including members of the PIAS (Protein inhibitor of activated STAT) family, this hydrophobic core is flanked by serine residues and a stretch of acidic residues. By using PIAS1 as a SUMO-binding model protein we could previously show that these serine residues are phosphorylated by the kinase CK2 and could demonstrate that this dictates binding of free SUMO and SUMO conjugates to PIAS1 (Stehmeier and Muller, 2009).
CK2-regulated phosphoSIM modules were also dissected in the tumor suppressor PML and the exosome component PMSCL1, indicating that these modules serve as general platforms that integrate CK2- and SUMO-regulated signaling networks.
The characterization of SIMs in PIAS and PML revealed a new regulatory layer for SUMO recognition by SIM modules. One aspect of our current project is to functionally characterize the phosphoSIM modules of PIAS family members.
Moreover, we aim to elucidate other mechanisms that regulate the dynamics of SUMO/SIM interactions and want to understand how this affects specific cellular pathways, in particular PIAS-mediated transcriptional processes.
Stehmeier, P. & Muller, S. (2009). Phospho-regulated SUMO interaction modules connect the SUMO system to CK2 signaling. Mol. Cell 33, 400-409.

The SUMO system in mammalian ribosome biogenesis

Ribosome biogenesis is a tightly controlled pathway that requires an intricate spatial and temporal interplay of protein networks. Most structural rRNA components are generated in the nucleolus and assembled into pre-ribosomal particles, which are transferred for further maturation to the nucleoplasm and cytoplasm. In mammalian cells, however, it is largely unclear what drives these processes.
Our previous and current work revealed a critical role for the SUMO-specific protease SENP3 in the control of nucleolar dynamics and ribosome biogenesis. In particular, we could show that SENP3 is critically involved in the maturation of the 28S rRNA and the nucleolar export of the 60S pre-ribosomal subunit (Haindl et al., 2008, Finkbeiner et al., 2011).
We now identified and characterized a novel SENP3-associated complex comprised of PELP1, TEX10 and WDR18 and demonstrate that this complex is involved in maturation and nucleolar release of the large ribosomal subunit.
We identified PELP1 and as a SENP3-sensitive targets of SUMO2 and provide evidence that the SUMO system determines the nucleolar partitioning of the PELP1-TEX10-WDR18 complex.
This work thus defines the PELP1-TEX10-WDR18 complex as a novel regulator of ribosome biogenesis and suggests that its SUMO-regulated distribution provides a mechanism to coordinate the rate of ribosome formation. We propose a model where the balanced SUMO conjugation/deconjugation controls the dynamic association of this complex with 60S pre-ribosomal particles.
We now aim to get mechanistic insights how sumoylation/desumoylation processes mediate the dynamics of pre-60S pre-ribosomal particles. Moreover, we want to understand how the SUMO system coordinates the rate of ribosome formation with the physiological state of the cell.
Haindl, M., Harasim, T., Eick, D. & Muller, S. (2008). The nucleolar SUMO-specific protease SENP3 reverses SUMO modification of nucleophosmin and is required for rRNA processing. EMBO Rep. 9, 273-279.

Finkbeiner, E., Haindl, M. & Muller S. (2011) The SUMO system controls nucleolar partitioning of a novel mammalian ribosome biogenesis complex. EMBO J., 30, 1067 – 1078.