Neuronal immunoproteasome and PFKFB3-forced glycolysis: key players in multiple sclerosis

In a recent study published in Cell, Woo et al. 1 investigated the role of the immunoproteasome and the metabolic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in neurons in the context of multiple sclerosis (MS)-related IFNγ signaling, finding new therapeutic targets for neurodegeneration in MS and possibly other related neuroinflammatory neurodegenerative disorders. The immunoproteasome is a variant of the constitutive proteasome, where the core catalytic subunits PSMB5 (β5), PSMB6 (β1), and PSMB7 (β2) are replaced by the inducible subunits PSMB8 (β5i), PSMB9 (β1i), and PSMB10 (β2i), which display slightly different hydrolytic profiles. The expression of the inducible subunits increases in most cell types in response to IFNγ, resulting in improved class I antigen processing. However, beyond this immune system function, the immunoproteasome has also been found to play specific regulatory roles, like redox signaling and oxidative stress, among others, in many cell types, including neurons, and the induction of the immunoproteasome in neurons has been implicated in different neurodegenerative diseases, as first reported for Huntington’s disease.2