IFN-gamma-induced immune adaptation of the proteasome system is an accelerated and transient response.
Peptide generation by the proteasome is rate-limiting in MHC class I-restricted antigen presentation in response to IFN-gamma. IFN-gamma-induced de novo formation of immunoproteasomes, therefore, essentially supports the rapid adjustment of the mammalian immune system. Here, we report that the molecular interplay between the proteasome maturation protein (POMP) and the proteasomal beta5i subunit low molecular weight protein 7 (LMP7) has a key position in this immune adaptive program. IFN-gamma-induced coincident biosynthesis of POMP and LMP7 and their direct interaction essentially accelerate immunoproteasome biogenesis compared with constitutive 20S proteasome assembly. The dynamics of this process is determined by rapid LMP7 activation and the immediate LMP7-dependent degradation of POMP. Silencing of POMP expression impairs recruitment of both beta5 subunits into the proteasome complex, resulting in decreased proteasome activity, reduced MHC class I surface expression, and induction of apoptosis. Furthermore, our data reveal that immunoproteasomes exhibit a considerably shortened half-life, compared with constitutive proteasomes. In consequence, our studies demonstrate that the cytokine-induced rapid immune adaptation of the proteasome system is a tightly regulated and transient response allowing cells to return rapidly to a normal situation once immunoproteasome function is no longer required.
Heink
Sylvia
S
Institute of Biochemistry, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Ludwig
Daniela
D
Kloetzel
Peter-M
PM
Krüger
Elke
E
D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D016207:Cytokines / Q000378:metabolism; D020868:Gene Silencing; D005805:Genes, MHC Class I / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007107:Immune System; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000378:metabolism*; D007700:Kinetics; D008285:Major Histocompatibility Complex; D018832:Molecular Chaperones / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D020798:Two-Hybrid System Techniques; D015854:Up-Regulation
D016207:Cytokines; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; C110856:proteasome maturation protein; D007371:Interferon-gamma; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex