S-Nitrosation and Ubiquitin-Proteasome System Interplay in Neuromuscular Disorders

Figure 2

S-nitrosation-induced cellular effects on ubiquitin-proteasome system. Nitric oxide (NO) can target each one of the three components indispensable for protein ubiquitination and subsequent degradation: the ubiquitinating machinery (E1, E2, and E3 enzymes), the protein substrate, and the proteasome (center of the circle). S-nitrosation can enhance the degradation rate of the protein substrate (point 1, e.g., 𝑂⁶-alkylguanyl-DNA alkyltransferase, AGT) or its ubiquitination (point 2). Conversely, S-nitrosation can (i) inhibit ubiquitin ligase activity of several E3s, such as Parkin and XIAP (point 3), (ii) affect ubiquitination directly, by changing protein structure, as demonstrated for Bcl2 and FLIP (point 4), or indirectly, by inhibiting enzyme activities of proteins acting as positive modifiers of ubiquitination (e.g., IKKβ, point 5), and (iii) directly impair protasome activity (point 6). Red ring: inhibitory effects; green ring: activating effects.