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.
Highlights
In eukaryotes, most integral membrane proteins are synthesized, integrated into the membrane, and folded properly in the endoplasmic reticulum (ER)
For selected lines exhibiting defects in rhodopsin 1 (Rh1) accumulation in the live imaging screening, the immunocytochemical distribution of Rh1 was investigated to evaluate the phenotype with respect to transport and morphogenesis (Table 2, Satoh et al, 2013)
Rh1 was not co-immunoprecipitated with EMC1::GFP from vitamin A-deficient photoreceptors accumulating immature Rh1 apoprotein in the ER. These results indicate that dPob and EMC1 are in a complex in vivo, as shown in yeast, and Cnx can be associated with the complex, which is consistent with the result of epistatic analysis; the stage at which dPob works on the expression of Rh1 apoprotein is close to that of Cnx
Summary
Most integral membrane proteins are synthesized, integrated into the membrane, and folded properly in the endoplasmic reticulum (ER). Molecular chaperones and folding enzymes are required for the folding of the integral membrane proteins in the ER. A comprehensive approach in yeast to identify genes required for protein folding in the ER identified the ER membrane protein complex (EMC), which comprises six subunits (Jonikas et al, 2009). Another report studying the comprehensive interaction map of ER-associated degradation (ERAD) machinery revealed that EMC contains four and three additional subunits in mammals and Drosophila, respectively (Christianson et al, 2011). The deletions of each emc gene causes the unfolded protein response (UPR), presumably caused by the accumulation of misfolded proteins (Jonikas et al, 2009). A recent study showed that EMC facilitates lipid transfer from ER to mitochondria (Lahiri et al, 2014)
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