Is GRP78 a Sensor of Cellular Secretory Activity?

Abstract

In eukaryotes, secreted proteins and membrane proteins are transported through two membrane-bound compartments consisting of the endoplasmic reticulum (ER) and Golgi complex. In the lumen of the ER they undergo covalent modification, folding and assembly which are prerequisites for efficient transport (1). These events are mediated by a complement of resident ER proteins. Studies on the development of secretory capacity indicate that cells respond to increases in the synthesis of secretory proteins by coordinately regulating the expression of resident ER proteins (2). The glucose regulated proteins (GRP), GRP78¹ and GRP94, may provide important insight into the mechanisms by which coordinate regulation of ER resident proteins may be achieved. The GRPs are transcriptionally activated by a variety of stress agents which inhibit processing and transport of secretory proteins from the ER (3,4). While little is known of the function of GRP94, GRP78 is known to bind stably to unprocessed, misfolded or unassembled proteins whose presence in the ER stimulates GRP expression (5). The GRPs also play an essential role under non-stress conditions since expression is constitutive in all mammalian tissues but is increased in cells active in protein secretion (2), and GRP78 is highly conserved in eukaryotes (6). To explain the regulation of GRPs and other resident ER proteins several groups have suggested the existence of a feedback mechanism whereby cells monitor the level of exported proteins in the ER and adjust the level of resident ER proteins accordingly (2,5). GRP78 has been proposed to function as such an ER sensor. In this paper I review the evidence for this proposal including genetic and biochemical similarities to the heat shock proteins (HSPs) and specifically to the 70 kD heat shock family (HSP70) of which GRP78 is a member.