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Dr. Tao Wang’s lab discovered a conserved mechanism which regulates Rhodopsin synthesis

Publication Date:2019/07/08

On July 1st, 2019, Dr. Tao Wang’s lab has published an article on the journal of 《Cell Death and Differentiation》which is titled “ER complex proteins are required for rhodopsin biosynthesis and photoreceptor survival in Drosophila and mice”. The author reported ER membrane complex (EMC) plays an important role in Rhodopsin synthesis and photoreceptor survival both in Drosophila and mice.

Retinitis Pigmentosa (RP) is a common hereditary progressive retinal degeneration disease, which affects 1 out of 3500 people. RP will eventually lead to blindness due to a gradually loss of cone cells, and no effective clinical treatment available so far. Mutations in Rhodopsin gene account for 25% of all the autosomal dominant RP cases. Thus, a better understanding of how Rhodopsin is regulated offers an opportunity to cure related RP diseases.

In this paper, the author isolated three independent emc mutants via a large-scale EMS screening. EMC, composed of ten subunits, is a highly conserved ER transmembrane protein complex, and functions in varied processes such as autophagy, viral infection, lung development and lipid transportation. Although EMC1 mutation has been identified in retinal degenerated patients, we still don’t know how EMC functions in mammalian visual system, nor do we know the way EMC regulates its substrates and different functions within EMC subunits.

The author found, emc mutants displayed decreased Rhodopsin protein level and absence of prolonged depolarization afterpotential (PDA). And EMC regulates Rhodopsin level through protein biosynthesis step rather than degradation process. TEM pictures show a retinal degeneration phenotype in emc mutant flies.

(Figure 1 Left: Rhodopsin decreased in emc mutant flies, Right: Rhodopsin decreased and mislocalized in Emc3 KO mice.)

(Figure 2 Loss of PDA in emc mutant flies.)

(Figure 3 Retinal degeneration in emc mutant flies.)

Next, the author generated a whole library of emc knockout flies and measured the importance of each EMC subunit in different context, ranging from animal viability, cellular viability, rhodopsin levels, and phototransduction. Also, based on proteomic analysis, the author claimed that different EMC subunits show discrepancy towards substrate selection, and thus might function differently in cells.

Finally, the author confirmed the importance of EMC in regulating Rhodopsin level and maintaining photoreceptor structure in mice. Knocking out Emc3 in photoreceptors leads to a decreased and mislocalized Rhodopsin protein, as well as degenerated photoreceptors, proving the conserved role of EMC in mammals.

This study established a conserved role for EMC to function in regulating Rhodopsin level and maintaining photoreceptor structure in both Drosophila and mice, and might provide a new solution for interfering retinitis pigmentosa.

Liangyao Xiong (2014 PTN project) from Dr. Tao Wang’s lab and Dr. Lin Zhang from Dr. Xianjun Zhu’s lab in Sichuan Provincial People’s Hospital are the co-first authors of this paper. Other contributors include Yeming Yang and Na Li (Dr. Xianjun Zhu’s lab), Dr. Wenjia Lai from National Center for Nanoscience and Technology, and Dr. Fengchao Wang from NIBS. Dr. Xianjun Zhu and Dr. Tao Wang are the co-corresponding authors of this paper. This study is supported by National Natural Science Foundation of China, National Key Scientific Research Program and Department of Science and Technology of Sichuan Province.