Well done to ESR Alexandra Papaioannou and her supervisor Eric Chevet on their excellent work that has been accepted for publication in The FEBS Journal.
The paper demonstrates that alterations of EDEM1 functions enhance ATF6 pro‐survival signaling.
Activating transcription factor 6 alpha (referred to as ATF6 hereafter) is an endoplasmic reticulum (ER)‐resident glycoprotein and one of the 3 sensors of the unfolded protein response (UPR). Upon ER stress, ATF6 is exported to the Golgi complex where it is cleaved by the S1P and S2P proteases thus releasing ATF6 cytosolic fragment and leading to the transcription of ATF6 target genes. In this study, they performed a phenotypic small interfering RNA (siRNA) screening to better characterize the ER mechanisms involved in ATF6 activation upon ER stress. This revealed that silencing of ER‐degradation enhancing alpha‐mannosidase‐like protein‐1 (EDEM1) increased the bioavailability of ER stress‐induced ATF6 export to the Golgi complex through the stabilization of the natively unstable ATF6 protein. Moreover, they characterized a somatic variant of EDEM1 (N198I) found in hepatocellular carcinoma that alters ATF6 signaling and might provide a selective advantage to the transforming cells. Hence, their work confirms the natively unstable nature of ATF6 and links this property to potentially associated pro‐oncogenic functions.
Great work Alexandra!