Basophil-specific and post-translational silencing of a major endoplasmic reticulum heat shock protein gp96 (grp94, HSP90b1) for TLR and integrin (80.7)

Abstract

Abstract Basophil has been implicated in anti-parasite defense, allergy and in polarizing TH2 response. However, little is known about its biological significance in vivo, due to lack of basic understanding of basophil developmental/functional cues. As an essential chaperone for multiple Toll-like receptors (TLRs) and integrins in the endoplasmic reticulum (ER), gp96 (grp94, HSP90b1) also participates in general protein homeostasis and in the ER unfolded protein response (UPR) to ensure cell survival during stress. No nucleic cells in mammals have been described to be naturally devoid of gp96. By genetically ablating gp96, we report herein that gp96 is dispensable for basophil development in vivo. Moreover, we found that gp96 was post-translationally cleaved in primary basophils leading to accumulation of a N-terminal ~50 kDa fragment of gp96 and up-regulation of several components of the UPR pathway. The alteration of gp96 was unique to basophils and was not observed in any other cell types including mast cells. Furthermore, we found that deletion of C-terminal domain of gp96 resulted in loss of its chaperone function. Our study revealed a remarkable biochemical event of gp96 silencing in basophils, arguing for the potential importance of shutting down gp96 post-translationally in regulating basophil development and function.