TANAKA Keiji INSTITUTE FOR ENZYME RESEARCH,THE UNIVERSITY OF TOKUSHIMA,ASSOCIATE PROFESSOR, 酵素科学研究センター, 助教授 (10108871)
YOKOTA Kinya UNIVERSITY HOSPITAL OF SCHOOL OF MEDICINE,THE UNIVERSITY OF TOKUSHIMA,ASSISTANT, 医学部・附属病院, 助手 (10274218)
|Budget Amount *help
¥2,100,000 (Direct Cost : ¥2,100,000)
Fiscal Year 1995 : ¥800,000 (Direct Cost : ¥800,000)
Fiscal Year 1994 : ¥1,300,000 (Direct Cost : ¥1,300,000)
The proteasome is a unusually large multifunctional protease complex consisting of multiple polypeptides, which catalyzes non-lysosomal, ATP-dependent selective breakdown of ubiquitinated proteins and is thought to be a putative processing enzyme responsible for major histocompatibility complex (MHC) class I-restricted antigen presentation. Recently, we reported that a major immunomodulatory cytokine, gamma interferon (gamma-IFN), induced not only marked synthesis of the MHC-encoded proteasome subunits LMP2 and LMP7, but also almost complete loss of two unidentified proteasome subunits tentatively designated as X and Y in various human cells, which alters the proteolytic specificity of proteasomes perhaps more appropriate for the immunological processing of endogenous antigens. Based on partial amino acid sequence analysis of X and Y,we suggested that subunit X is a proteasomal subunit similar to LMP7, and that subunit Y is identical to the LMP2-related proteasomal subunit delta. Final
ly, molecular cloning of cDNAs encoding X and Y showed that these X and Y are a novel class of proteasomal subunits with high homology to LMP7 and LMP2, respectively. Moreover, recently we found two novel proteasome subunits expressed reciprocally in response to interferon-gamma. Molecular cloning of a cDNA encoding one subunit designated as Z down-regulated by interferon-gamma showed that it is a novel proteasomal subunit with high homology to MECL1, which is markedly induced by interferon-gamma (Submitted for publication). Thus, interferon-gamma may induce subunit replacements of not only X and Y by LMP7 and LMP2, respectively, but also of Z by MECL1, producing proteasomes responsible for major histocompatibility complex (MHC) class I-restricted antigen presentation.
The primary structures of two proteins that comprise PA28, an activator of the 20S proteasome, have been determined by cDNA cloning and sequencing. These protein subunits, termed PA28a and PA28b, are about 50% identical to one another and are highly conserved between rat and human.