Sumoylation in Physiology, Pathology and Therapy

Abstract

Sumoylation is an essential post-translational modification that has evolved to regulate intricate networks within emerging complexities of eukaryotic cells. Thousands of target substrates are modified by SUMO peptides, leading to changes in protein function, stability or localization, often by modulating interactions. At the cellular level, sumoylation functions as a key regulator of transcription, nuclear integrity, proliferation, senescence, lineage commitment and stemness. A growing number of prokaryotic and viral proteins are also emerging as prime sumoylation targets, highlighting the role of this modification during infection and in immune processes. Sumoylation also oversees epigenetic processes. Accordingly, at the physiological level, it acts as a crucial regulator of development. Yet, perhaps the most prominent function of sumoylation, from mammals to plants, is its role in orchestrating organismal responses to environmental stresses ranging from hypoxia to nutrient stress. Consequently, a growing list of pathological conditions, including cancer and neurodegeneration, have now been unambiguously associated with either aberrant sumoylation of specific proteins and/or dysregulated global cellular sumoylation. Therapeutic enforcement of sumoylation can also accomplish remarkable clinical responses in various diseases, notably acute promyelocytic leukemia (APL). In this review, we will discuss how this modification is emerging as a novel drug target, highlighting from the perspective of translational medicine, its potential and limitations.

Keywords: cancer; infection; neurodegeneration; post-translational modification; small ubiquitin-like modifier; stress; ubiquitin.

Figure 1

Similarities and disparities between ubiquitin (A) and SUMO (B), highlighted from a standpoint of structure, functional capabilities and the enzymatic machinery involved. Although SUMO1 shares an 18% amino-acid sequence identity with ubiquitin, the three-dimensional structures of SUMO1, SUMO2/3 and ubiquitin are remarkably similar, all featuring the central ubiquitin core that folds into a “ββαββαβ” pattern. The structure of SUMO1 is unique in that a flexible N-terminal extension protrudes from this central core (highlighted in dark blue). Images were generated by PyMOL (SUMO1 PDB: 2n1v, SUMO2/3 PDB: 2n1w, ubiquitin PDB: 1ubq).