Olfactory receptor accessory proteins play crucial roles in receptor function and gene choice

Abstract

<p>Understanding how we detect our environment is crucial to understanding how life evolved and now functions. Volatile chemicals from our surroundings are sensed by our olfactory system, a primitive sense that organisms have relied on for survival for millions of years. Mammals express a large family of odorant receptor (OR) genes in the sensory neurons in the nose that mediate this chemosensation. Each mature olfactory sensory neuron (OSN) expresses a single allele of a single OR gene at one time although in the absence of a functional gene OSNs can switch to another OR gene. A functional OR can inhibit the expression of another OR by co-opting the unfolded protein response (UPR). How OSNs make their initial OR gene choice and the mechanisms by which the ORs interact with UPR factors remain unknown. </p><p>In this study, I make use of a double knock out mouse that has RTP1 and RTP2, proteins required for the efficient surface trafficking of ORs in heterologous cells, to study the gene regulation of ORs during a large-scale perturbation of the trafficking of ORs to the cell surface. We initially generate and validate the RTP1 and RTP2 double knock out mouse (RTP1,2DKO) and show that consistent with our heterologous expression system, the mutant mice have OR trafficking defects. These OR trafficking defects give rise to higher rates of cell death and the mutant mice have fewer mature OSNs. Surprisingly we identified a subset of ORs that were overrepresented in the RTP1,2DKO animals. Some of these ORs can target the cell surface in the absence of the RTPs. This finding gave rise to two cohorts of ORs, those that are underrepresented in the mutants and presumably dependent on the RTPs for cell surface trafficking and ORs that are overrepresented in RTP1,2DKO. We show that OSNs expressing underrepresented receptors were more likely to be unable to terminate UPR had a higher tendency to switch the OR it was expressing. Using these two cohorts we showed that the trafficking of ORs to the cell surface is a crucial step in the stabilization of the expression of the OR. In the absence of this cell surface trafficking the OSN is unable to terminate the UPR pathway and either undergoes cell death or OR gene switching.</p>