Title:
BAG-6/Scythe/BAT3 is essential for selective elimination of defective proteasomal substrates.

Hiroyuki, Kawahara, Ph.D. Professor, Department of Biological Sciences, Tokyo Metropolitan University , Tokyo

Abstract:
The importance of protein quality control is best exemplified by a number of human disorders that can result from the accumulation of misfolded proteins. Thus, understanding the precise mechanisms of misfolded protein metabolism, as well as co-translational degradation of defective proteins in mammalian cells, should be a primary important. It is known that ubiquitin-mediated protein quality control is an essential process for monitoring protein folding and endorsing defective proteins for degradation. However, owing to the redundancy of substrate recognition pathway, entire pictures of substrate recruitment to the 26S proteasome in the ubiquitin system have not been adequately given to date.
　 BAG-6/Scythe/BAT3 was originally identified as a novel gene located within the human major histocompatibility complex and anti-apoptotic ubiquitin-like protein , although the mechanisms of its function remain largely obscure. In this study, we provide a set of evidence that BAG-6 involved in degradation of polyubiquitinated proteasomal substrates in mammalian cells. Importantly, BAG-6-associated polyubiquitinated species are newly synthesized defective ribosomal products (DRiPs) and BAG-6 plays a crucial role in their proteasome-mediated degradation. BAG-6 offers a protective role against cell death induced by accumulation of aberrant proteins. Furthermore, we showed that knockdown of BAG-6 results in the suppressed presentation of MHC class I on the cell surface, a procedure known to be affected by the efficiency of metabolism of defective ribosomal products (DRiPs).
　 Based of those findings, w e propose that BAG-6 is a novel tethering factor that mediates selective elimination of defective nascent chain polypeptides in mammalian cells. Such novel functions of BAG-6 might offer a significant protective role for diseases caused by defects in protein quality control.