SUMO Regulation of Ion Channels in Health and Disease

Abstract

The small ubiquitin-like modifier (SUMO) protein pathway governs a panoply of vital biological processes including cell death, proliferation, differentiation, metabolism, and signal transduction by diversifying the functions, half-lives, and partnerships of target proteins in situ. More recently, SUMOylation has emerged as a key regulator of ion homeostasis and excitability across multiple tissues due to the regulation of a plethora of ion channels expressed in a range of tissue subtypes. Altogether, the balance of SUMOylation states among relevant ion channels can result in graded biophysical effects that tune excitability and contribute to a range of disease states including cardiac arrhythmia, epilepsy, pain transmission, and inflammation. Here, we consolidate these concepts by focusing on the role of ion channel SUMOylation in the central nervous system, peripheral nervous system, and cardiovascular system. In addition, we review what is known about the enigmatic factors that regulate the SUMO pathway and consider the emerging role of small molecule SUMO modulators as potential therapeutics in a range of diseases.

Keywords: SUMOylation; UbL; Ubc9; ion channels; posttranslational modification.

Figure 1.. The SUMO-pathway.

1. ProSUMO is cleaved at the C-terminus by SENP to reveal a diglycine motif. 2. SUMO is activated by the E1 enzyme complex (SAE1 + SAE2) in an ATP-dependent manner. 3. SUMO is coupled to Cys173 on SAE2 via a thiol linkage then transferred to Cys93 of the E2 conjugating enzyme, Ubc9 via a transesterification reaction. 4. The SUMO-Ubc9 complex recognizes a target lysine in a SUMOylation motif (ψ-K-X-E/D) on the target protein, in the presence or absence of an E3 ligase. SUMO is covalently coupled to the ε-amine group of the target lysine and thereby evokes changes in protein function. In the case of ion channels, these could be biophysical properties, trafficking dynamics or protein-protein interactions that tune cellular excitability. 5. SUMO can be deconjugated from the target protein by the isopeptidase activity of a deSUMOylating enzyme, such as a SENP. SUMO can then reenter this pathway at position 2. This readily reversible PTM is active at the plasma membrane to regulate the activity of ion channels in situ.

Figure 2.. SUMO-regulation of cardiac action potential.

The cardiac action potential is organized into 4-phases with contributions from distinct groups of channels required to depolarize (phase 0), repolarize (phases 1, 2, 3) and stabilize the membrane potential (phase 4). The distribution and relative contribution of the channels can vary with species, location in the myocardium, and disease status. Channels that are SUMO-regulated in cardiomyocytes are shown. See also Table 3.