The misfolded proteins or those that have failed to become post-translationally modified in the endoplasmic reticulum (ER), together with unassembled members of multiprotein complexes are discarded by ER-association degradation (ERAD). This process involves recognition, polyubiquitination, and retrotranslocation to the cytosol of the targeted proteins, followed by proteasomal degradation. It has been reported that the ER degradation-enhancing alpha-mannosidase-like proteins 1, 2, & 3 (EDEM1-3) that belong to the Class I alpha1,2-mannosidase family (glycosylhydrolase family 47) are essential in recognition and targeting of the terminally misfolded glycoproteins. However, their role in a multicellular organism has not been yet addressed, and we are investigating the redundancy of th e C. elegans EDEMs in the degradation process. Similarity searches have identified orthologs of the mammalian EDEM 13 in C. elegans (C47E12.5, F10C2.5 and ZC506.1, respectively), whose putative proteins share 46, 39, and 41% amino acid sequence identity, respectively, and similar domain architecture. Analysis of
edem-1-3 genes expression by quantitative real-time PCR showed that
edem-2 mRNA is the less abundant. Inactivation of any of the single or double gene expression does not exhibit a dramatic phenotype in ER non-stress conditions. However, we found that inactivation increased the sensitivity of worms to ER stress; thus, they show intensive degradation of intestine and various degrees of developmental arrest at larval stage 2 (L2). Our observations suggest a partially redundant function for the three EDEMs in survival upon ER-stress. Moreover, depletion of any of the C. elegans EDEMs upregulates the expression of ER chaperone BiP, an indicator of the ER stress. This suggests that in the absence of any EDEM protein a n ER stress that triggers Unfolded Protein Response (UPR) is induced.