Olfactory Neurons Get Stressed Out

Science Signaling  22 Oct 2013:
Vol. 6, Issue 298, pp. ec255
DOI: 10.1126/scisignal.2004827

Mammals detect odors through specialized G protein–coupled receptors, called olfactory receptors (ORs), which are located in the olfactory epithelium. Each mature olfactory sensory neuron (OSN) expresses only one OR-encoding gene from over 1000 possibilities. In immature OSNs, OR genes are epigenetically silenced and the chromatin-directed lysine demethylase LSD1 derepresses a single stochastically selected OR-encoding gene. To prevent the expression of additional OR genes, OR proteins inhibit LSD1 activity, in part through activation of adenylyl cyclase 3 (ADCY3). Because once selected OR-encoding genes are rapidly induced and the encoded proteins are abundant and LSD1 is inhibited too rapidly for OR signaling to occur, Dalton et al. hypothesized that nascent OR polypeptides may trigger the unfolded protein response (UPR) in the endoplasmic reticulum. One consequence of activation of the UPR is phosphorylation of the translation initiation factor eIF2α by the kinase eIF2αK3 (also known as PERK) and increased activity of the transcription factor ATF5. In the mouse olfactory epithelium, like LSD1, ATF5 was primarily detected in immature OSNs, whereas ADCY3 was detected in mature OSNs. Transgenic mice that lack expression of all OR-encoding genes had reduced nuclear ATF5, whereas transgenic overexpression of a single OR gene cluster in these mice partially restored ATF5 abundance in OSNs. Atf5-knockout increased LSD1 abundance, decreased ADCY3 abundance in the olfactory epithelium, and reduced the numbers of OSNs. Lineage analysis showed that Atf5 knockout inhibited stable OR selection in mature OSNs. The olfactory epithelia of mice with a mutation in the phosphorylation site of eIF2α had reduced ADCY3 and active ATF5, whereas transgenic overexpression of nuclear ATF5 in immature OSNs of these mice restored ADCY3 abundance. Similarly, the olfactory epithelia of Perk-knockout mice had reduced ATF5 and ADCY3 abundance and loss of markers associated with mature OSNs. Adcy3-knockout mice, which have increased LSD1 in OSNs and defects in stable OR selection, showed expanded immunoreactivity for active ATF5 in mature OSNs. Together, these results support a model whereby the stochastic selection and production of a single OR activates the UPR. In response to this stress, ADCY3 increases in abundance, which inhibits LSD1 in mature OSNs to shut off OR-encoding gene expression and OR protein production to alleviate the ER stress, which leads to OR self-selection without requiring activation of the OR.

R. P. Dalton, D. B. Lyons, S. Lomvardas, Co-opting the unfolded protein response to elicit olfactory receptor feedback. Cell 155, 321–332 (2013). [PubMed]