Co-Opting the Unfolded Protein Response to Elicit Olfactory Receptor Feedback

Olfactory receptor (OR) expression requires the transcriptional activation of 1 out of 1,000s of OR alleles and a feedback signal that preserves this transcriptional choice. The mechanism by which olfactory sensory neurons (OSNs) detect ORs to signal to the nucleus remains elusive. Here, we show that OR proteins generate this feedback by activating the unfolded protein response (UPR). OR expression induces Perk-mediated phosphorylation of the translation initiation factor eif2α causing selective translation of activating transcription factor 5 (ATF5). ATF5 induces the transcription of adenylyl cyclase 3 (Adcy3), which relieves the UPR. Our data provide a role for the UPR in defining neuronal identity and cell fate commitment and support a two-step model for the feedback signal: (1) OR protein, as a stress stimulus, alters the translational landscape of the OSN and induces Adcy3 expression; (2), Adcy3 relieves that stress, restores global translation, and makes OR choice permanent. [Display omitted] •Olfactory receptors cause ER stress and activate Perk in olfactory neurons•Perk phosphorylates Eif2a, which induces translation of a nuclear isoform of ATF5•ATF5 promotes Adenylyl cyclase 3 expression•Adenylyl cyclase 3 relieves the ER stress and locks olfactory receptor choice The signaling pathway that locks in the expression of a single olfactory receptor in a given olfactory neuron is elicited by an OR-induced unfolded protein response in the ER.