The Proteasome System in Infection: Impact of b5 and LMP7 on Composition, Maturation and Quantity of Active Proteasome Complexes

Proteasomes are the major enzyme complexes for non-lysosomal protein degradation in eukaryotic cells. Mammals express two sets of catalytic subunits: the constitutive subunits b1, b2 and b5 and the immunosubunits LMP2 (b1i), MECL-1 (b2i) and LMP7 (b5i). The LMP7-propeptide (proLMP7) is required for optimal maturation of LMP2/MECL-1-containing precursors to mature immunoproteasomes, but can also mediate efficient integration into mixed proteasomes containing b1 and b2. In contrast, the b5-propeptide (prob5) has been suggested to promote preferential integration into b1/b2-containing precursors, consequently favouring the formation of constitutive proteasomes. Here, we show that prob5 predominantly promotes integration into LMP2/MECL-1-containing precursors in IFNc-stimulated, LMP7-deficient cells and infected LMP7-deficient mice. This demonstrates that prob5 does not direct preferential integration into b1/b2-containing precursors, but instead promotes the formation of mixed LMP2/MECL-1/b5 proteasomes under inflammatory conditions. Moreover, the propeptides substantially differ in their capacity to promote proteasome maturation, with proLMP7 showing a significantly higher chaperone activity as compared to prob5. Increased efficiency of proteasome maturation mediated by proLMP7 is required for optimal MHC class I cell surface expression and is equally important as the catalytic activity of immunoproteasomes. Intriguingly, induction of LMP7 by infection not only results in rapid exchange of constitutive by immunosubunits, as previously suggested, but also increases the total proteasome abundance within the infected tissue