Enhanced rate of degradation of basic proteins by 26S immunoproteasomes.
Immunoproteasomes are alternative forms of proteasomes specialized in the generation of MHC class I antigenic peptides and important for efficient cytokine production. We have identified a new biochemical property of 26S immunoproteasomes, namely the ability to hydrolyze basic proteins at greatly increased rates compared to constitutive proteasomes. This enhanced degradative capacity is specific for basic polypeptides, since substrates with a lower content in lysine and arginine residues are hydrolyzed at comparable rates by constitutive and immunoproteasomes. Crucially, selective inhibition of the immunoproteasome tryptic subunit β2i strongly reduces degradation of basic proteins. Therefore, our data demonstrate the rate limiting function of the proteasomal trypsin-like activity in controlling turnover rates of basic protein substrates and suggest new biological roles for immunoproteasomes in maintaining cellular homeostasis by rapidly removing a potentially harmful excess of free histones that can build up under different pathophysiological conditions.
Department of Veterinary Sciences, University of Turin, Grugliasco 10095, Italy.
Mary
M
Raule
Department of Veterinary Sciences, University of Turin, Grugliasco 10095, Italy.
Fulvia
F
Cerruti
Department of Veterinary Sciences, University of Turin, Grugliasco 10095, Italy. Electronic address: paolo.cascio@unito.it.
Paolo
P
Cascio
D000818:Animals; D006657:Histones / Q000378:metabolism; D006868:Hydrolysis / Q000187:drug effects; D007700:Kinetics; D007976:Leupeptins / Q000494:pharmacology; D008970:Molecular Weight; D010455:Peptides / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000276:immunology*; D059748:Proteolysis / Q000187:drug effects; D011817:Rabbits; D014357:Trypsin / Q000378:metabolism
D006657:Histones; D007976:Leupeptins; D010455:Peptides; D014357:Trypsin; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C032854:leupeptin
Histones; Immunoproteasome; MBP; Proteasome; Proteolysis; Trypsin-like activity