Growth retardation in mice lacking the proteasome activator PA28γ

The proteasome activator PA28 binds to both ends of the central catalytic machine, known as the 20 S proteasome, in opposite orientations to form the enzymatically active proteasome. The PA28 family is composed of three members designated alpha, beta, and gamma; PA28 alpha and PA28 beta form the heteropolymer mainly located in the cytoplasm, whereas PA28 gamma forms a homopolymer that predominantly occurs in the nucleus. Available evidence indicates that the heteropolymer of PA28 alpha and PA28 beta is involved in the processing of intracellular antigens, but the function of PA28 gamma remains elusive. To investigate the role of PA28 gamma in vivo, we generated mice deficient in the PA28 gamma gene. The PA28 gamma-deficient mice were born without appreciable abnormalities in all tissues examined, but their growth after birth was retarded compared with that of PA28 gamma(+/-) or PA28 gamma(+/+) mice. We also investigated the effects of the PA28 gamma deficiency using cultured embryonic fibroblasts; cells lacking PA28 gamma were larger and displayed a lower saturation density than their wild-type counterparts. Neither the expression of PA28 alpha/beta nor the subcellular localization of PA28 alpha was affected in PA28 gamma(-/-) cells. These results indicate that PA28 gamma functions as a regulator of cell proliferation and body growth in mice and suggest that neither PA28 alpha: nor PA28 beta compensates for the PA28 gamma deficiency.