dPob/EMC is essential for biosynthesis of rhodopsin and other multi-pass membrane proteins in Drosophila photoreceptors

Abstract

In eukaryotes, most integral membrane proteins are synthesized, integrated into the membrane, and folded properly in the endoplasmic reticulum (ER). We screened the mutants affecting rhabdomeric expression of rhodopsin 1 (Rh1) in the Drosophila photoreceptors and found that dPob/EMC3, EMC1, and EMC8/9, Drosophila homologs of subunits of ER membrane protein complex (EMC), are essential for stabilization of immature Rh1 in an earlier step than that at which another Rh1-specific chaperone (NinaA) acts. dPob/EMC3 localizes to the ER and associates with EMC1 and calnexin. Moreover, EMC is required for the stable expression of other multi-pass transmembrane proteins such as minor rhodopsins Rh3 and Rh4, transient receptor potential, and Na+K+-ATPase, but not for a secreted protein or type I single-pass transmembrane proteins. Furthermore, we found that dPob/EMC3 deficiency induces rhabdomere degeneration in a light-independent manner. These results collectively indicate that EMC is a key factor in the biogenesis of multi-pass transmembrane proteins, including Rh1, and its loss causes retinal degeneration.DOI: http://dx.doi.org/10.7554/eLife.06306.001

EMC3 coordinates surfactant protein and lipid homeostasis required for respiration

“…In Saccharomyces cerevisiae, deletion of Emc1-6 activated the sensor of misfolded proteins, Ire1p, and induced Hac1p splicing and the UPR (8). In Drosophila, loss of Emc3 in the retina activated IreI/Xbp1 and eIF2α phosphorylation (12). Consistent with those findings, we found that deletion of Emc3 in AT2 cells activated 2 of the 3 branches of the UPR, including IRE1α/XBP1 and PERK/eIF2α, as indicated by XBP1 and ATF4 activities, respectively.…”

“…Work in Danio (13), Caenorhabditis elegans (10, 11), and Drosophila (12) demonstrated that EMCs are critical for the biogenesis of multipass transmembrane proteins, but not for secreted proteins or type I single-pass transmembrane proteins. Consistent with these findings, our data demonstrated that EMC3 and other EMC subunits directly bound to and stabilized ABCA3, a 12-pass transmembrane protein (Figure 4).…”

“…Emc1, Emc2, and Emc3 form a complex with ER-associated degradation (ERAD) pathway components Ubac2 and Derlin-2, indicating a close link between the EMC and ERAD (9). Moreover, EMCs are essential for the assembly of several multipass membrane proteins including nicotinic acetylcholine receptors (AChRs) in Caenorhabditis elegans (10,11) and rhodopsin in Drosophila (12) and Danio (13). Despite its involvement in important cellular processes, the functions of Emc3 in vertebrate development and organ function are unclear.…”

Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics

“…The EMC is needed for transmembrane protein folding (Jonikas et al, 2009) and has been implicated in regulating the expression of the rhodopsin receptor in flies (Satoh et al, 2015) as well as orchestrating the transfer of lipids from the ER to the mitochondria in yeast (Lahiri et al, 2014). Notably, a pooled CRISPR/Cas9 screen for WNV host factors found three components of the EMC to be needed for WNVinduced cell death but not for viral replication (Ma et al, 2015).…”

The ubiquitous and ancient ER membrane protein complex (EMC): tether or not?

“…It has also been shown that the EMC is an ER-mitochondria tether in S. cerevisiae that interacts with the outer membrane protein Tom5 of the TOM (Translocase of the Mitochondrial Outer Membrane) complex ( Lahiri et al , 2014). Most recently, the EMC has been implicated in the proper assembly of multi-pass transmembrane (TM) proteins ( Satoh et al , 2015). These recent findings suggest that EMC involvement in ERAD may be due to secondary effects, as cells devoid of EMC components may result in either disruption of ER-mitochondria tethering, or the misfolding of multipass membrane proteins.…”