Modulators of the activation of the proteasome by PA28 (11S reg).
The degradation of chromogenic substrates and oligopeptides by the 20S proteasome is markedly enhanced and the generation of antigens for presentation by the MHC class-I system is facilitated by combination with an activator protein known as PA28 or 11S reg. We have described the properties of a PA28-proteasome modulator, N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinol which shifts the pathway of peptide hydrolysis by the activated proteasome to products terminating in an acidic amino acid at the expense of products terminating in a hydrophobic amino acid. We now report that piperazinyl phenothiazines and several other antipsychotic drugs modulate the PA28-20S activated proteasome in an opposite manner. Fluphenazine, trifluoperazine and prochlorperazine antagonize the peptidylglutamyl peptide bond hydrolyzing activity of the activated proteasome much more strongly than the chymotrypsinlike activity. The chicken ovalbumin immunodominant epitope SIINFEKL is degraded by the activated proteasome to SIINFE and SIINF in approximately equimolar amounts. Piperazinyl phenothiazines promote formation of SIINF whereas Psi-ol promotes formation of SIINFE. PA28- proteasome modulators by modifying the profile of peptides produced by the activated proteasome, may either enhance or suppress the immune response.
Wilk
S
S
Department of Pharmacology, Mount Sinai School of Medicine, New York, NY 10029, USA. S_Wilk@smtplink.mssm.edu
Chen
W E
WE
Magnusson
R P
RP
D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D002645:Chickens; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005476:Fluphenazine / Q000494:pharmacology; D016056:Immunodominant Epitopes / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism*
D014150:Antipsychotic Agents; D016056:Immunodominant Epitopes; D009097:Multienzyme Complexes; D009842:Oligopeptides; D011506:Proteins; D010047:Ovalbumin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D005476:Fluphenazine; D004121:Dimethyl Sulfoxide