title: The proteasome system in infection: impact of β5 and LMP7 on composition, maturation and quantity of active proteasome complexes.
abstract: Proteasomes are the major enzyme complexes for non-lysosomal protein degradation in eukaryotic cells. Mammals express two sets of catalytic subunits: the constitutive subunits β1, β2 and β5 and the immunosubunits LMP2 (β1i), MECL-1 (β2i) and LMP7 (β5i). 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 β1 and β2. In contrast, the β5-propeptide (proβ5) has been suggested to promote preferential integration into β1/β2-containing precursors, consequently favouring the formation of constitutive proteasomes. Here, we show that proβ5 predominantly promotes integration into LMP2/MECL-1-containing precursors in IFNγ-stimulated, LMP7-deficient cells and infected LMP7-deficient mice. This demonstrates that proβ5 does not direct preferential integration into β1/β2-containing precursors, but instead promotes the formation of mixed LMP2/MECL-1/β5 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 proβ5. 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. Hence our data identify a novel LMP7-dependend mechanism to enhance the activity of the proteasome system in infection, which is based on the high chaperone activity of proLMP7 and relies on accelerated maturation of active proteasome complexes.
authors: Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors: Thorsten
authors: T
authors: Joeris
authors: Nicole
authors: N
authors: Schmidt
authors: David
authors: D
authors: Ermert
authors: Petra
authors: P
authors: Krienke
authors: Alexander
authors: A
authors: Visekruna
authors: Ulrike
authors: U
authors: Kuckelkorn
authors: Stefan H E
authors: SH
authors: Kaufmann
authors: Ulrich
authors: U
authors: Steinhoff
mesh_terms: D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000494:pharmacology; D008087:Listeria / Q000187:drug effects / Q000502:physiology; D008088:Listeriosis / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000172:deficiency / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D015395:Histocompatibility Antigens Class I; D009097:Multienzyme Complexes; D011498:Protein Precursors; D021122:Protein Subunits; D012333:RNA, Messenger; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex; C490920:Psmb10 protein, mouse; C478802:Psmb5 protein, mouse