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Defective rhodopsin homeostasis is one of the major causes of retinal degeneration, including the disease Retinitis pigmentosa. To identify cellular factors required for the biosynthesis of rhodopsin, we performed a genome-wide genetic screen in Drosophila for mutants with reduced levels of rhodopsin. We isolated loss-of-function alleles in endoplasmic reticulum membrane protein complex 3 (emc3), emc5, and emc6, each of which exhibited defective phototransduction and photoreceptor cell degeneration. EMC3, EMC5, and EMC6 were essential for rhodopsin synthesis independent of the ER associated degradation (ERAD) pathway, which eliminates misfolded proteins. We generated null mutations for all EMC subunits, and further demonstrated that different EMC subunits play roles in different cellular functions. Conditional knockout of the Emc3 gene in mice led to mislocalization of rhodopsin protein and death of cone and rod photoreceptor cells. These data indicate conserved roles for EMC subunits in maintaining rhodopsin homeostasis and photoreceptor function, and suggest that retinal degeneration may also be caused by defects in early biosynthesis of rhodopsin.

The recycling of neurotransmitters is essential for sustained synaptic transmission. In Drosophila, histamine recycling is required for visual synaptic transmission. Synaptic histamine is rapidly taken up by laminar glia, and is converted to carcinine. After delivered back to photoreceptors, carcinine is hydrolyzed to release histamine and β-alanine. This histamine is repackaged into synaptic vesicles, but it is unclear how the β-alanine is returned to the laminar glial cells. Here, we identified a new β-alanine transporter, which we named BalaT (Beta-alanine Transporter). Null balat mutants exhibited lower levels of β-alanine, as well as less β-alanine accumulation in the retina. Moreover, BalaT is expressed and required in retinal pigment cells for maintaining visual synaptic transmission and phototaxis behavior. These results provide the first genetic evidence that retinal pigment cells play a critical role in visual neurotransmission, and suggest that a BalaT-dependent β-alanine trafficking pathway is required for histamine homeostasis and visual neurotransmission. DOI: http://dx.doi.org/10.7554/eLife.29146.001, eLife digest Neurons transmit information around the body in the form of electrical signals, but these signals cannot cross the gaps between neurons. To send a message to its neighbor, a neuron releases a molecule known as a neurotransmitter into the gap between the cells. The neurotransmitter binds to proteins on the recipient neuron and triggers new electrical signals inside that cell. When the message has been received, the neurotransmitter molecules are returned to the first neuron so that they can be reused. This recycling is particularly important in the visual system, where neurons communicate via rapid-fire signaling. In fruit flies, for example, light-sensitive neurons in the eye known as photoreceptors release a neurotransmitter called histamine when they detect light. Supporting cells called laminar glia take up any leftover histamine and combine it with another molecule known as β-alanine to form a larger molecule. The photoreceptors absorb this larger molecule and break it back down into histamine and β-alanine. However, it is not clear how the β-alanine returns to the glia to allow this cycle to continue. Many molecules rely on so-called “transporter” proteins to help them move into or out of cells. To identify transporters that might help to move β-alanine, Han, Xiong et al. prepared a list of fruit fly genes that encode transporter proteins found inside the insect’s head. Testing the resulting proteins in a cultured cell system revealed that one of them was able to transport β-alanine. This protein, named BalaT, is found in another type of support cell called retinal pigment cells. Mutant flies that cannot produce BalaT are blind because their photoreceptors have problems in transmitting information to other neurons. Han, Xiong et al. propose that BalaT transports β-alanine from photoreceptors to retinal pigment cells, which then pass β-alanine on to the laminar glia. Follow-up studies are required to find out exactly how the laminar glia take up histamine. DOI: http://dx.doi.org/10.7554/eLife.29146.002