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Motor Protein MYO1C Is Critical for Photoreceptor Opsin Trafficking and 2 Vision 3 4 Authors: Ashish K

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Motor Protein MYO1C Is Critical for Photoreceptor Opsin Trafficking and 2 Vision 3 4 Authors: Ashish K bioRxiv preprint doi: https://doi.org/10.1101/2020.06.02.129890; this version posted June 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Title: Motor Protein MYO1C is Critical for Photoreceptor Opsin Trafficking and 2 Vision 3 4 Authors: Ashish K. Solanki1, Elisabeth Obert2, Stephen Walterhouse1, Ehtesham Arif1, 5 Bushra Rahman1, Joshua H. Lipschutz1,3, Jeffery Sundstrom4, Barbel Rohrer2,3, Shahid 6 Husain2, Glenn P. Lobo1,2* and Deepak Nihalani1* 7 8 Affiliations: 1Department of Medicine, Medical University of South Carolina, 9 Charleston, SC, 29425, USA. 2Department of Ophthalmology, Medical University of 10 South Carolina, Charleston, SC, 29425, USA. 3Ralph H. Johnson VA Medical Center, 11 Division of Research, Charleston, SC 29420, USA. 4Penn State Eye Center, 200 12 Campus Dr., Suite 800, Hershey, PA 17033. USA. 13 14 15 *Corresponding Authors 16 *Glenn P. Lobo, Ph.D. 17 Assistant Professor of Medicine 18 Department of Medicine 19 70 President Road 20 Drug Discovery Building DDB513 21 Charleston, SC 29425 22 Office: 843-876-2371 23 Fax: 843-792-8399 24 Email: [email protected] 25 26 27 *Deepak Nihalani, Ph.D. 28 Associate Professor of Medicine 29 Department of Medicine 30 70 President Road 31 Drug Discovery Building DDB514 32 Charleston, SC 29425 33 Office: 843-792-7659 34 Fax: 843-792-8399 35 Email: [email protected] 36 37 38 39 Keywords: Motor protein, Myosin, MYO1C, Opsins, Photoreceptor, Outer Segments, 40 Photoreceptor Cell Degeneration, Trafficking, Vision. 41 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.02.129890; this version posted June 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 42 Abstract 43 Unconventional myosins linked to deafness are also proposed to play a role in retinal 44 physiology. However, their direct role in photoreceptor structure and function remains 45 unclear. Herein, we demonstrate that systemic loss of the unconventional myosin 46 MYO1C in mice affected opsin trafficking and photoreceptor survival, leading to vision 47 loss. Electroretinogram analysis of Myo1c knockout (Myo1c-KO) mice showed a 48 progressive loss of rod and cone function. Immunohistochemistry and binding assays 49 demonstrated MYO1C localization to photoreceptor inner and outer segments (OS) and 50 identified a direct interaction of rhodopsin with the MYO1C cargo domain. In Myo1c-KO 51 retinas, rhodopsin mislocalized to rod inner segments and the cell bodies, while cone 52 opsins in OS showed punctate staining. In aged mice, the histological and ultrastructural 53 examination of Myo1c-KO retinas showed a progressively degenerating photoreceptor 54 OS phenotype. These results demonstrate that MYO1C is critical for opsin trafficking to 55 the photoreceptor OS and normal visual function. 56 57 58 59 60 61 62 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.02.129890; this version posted June 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 63 Introduction 64 Protein trafficking within the photoreceptors must occur efficiently and at high fidelity for 65 photoreception, structural maintenance and overall retinal cell homeostasis. 66 Additionally, it is well known that proper opsin trafficking is tightly coupled to 67 photoreceptor cell survival and function [1-9]. However, the cellular events, including 68 signaling pathways and trafficking events that participate in retinal injuries due to 69 improper protein trafficking to the photoreceptor outer segments (OS), are not yet fully 70 understood. While many proteins are known to play an essential role in retinal cell 71 development and function, the involvement of motor proteins in eye biology is less 72 understood. Identification of genetic mutations in the Myo7a gene associated with 73 retinal degeneration in Usher syndrome suggests that unconventional myosins play a 74 critical role in retinal pigmented epithelium (RPE) and photoreceptor cell function [10, 75 11]. Unconventional myosins are motor proteins that are proposed to transport 76 membranous organelles along the actin filaments in an ATP-dependent manner, and 77 additional roles are currently being uncovered [12-14]. The loss of Myo7a primarily 78 affects RPE and OS phagocytosis leading to retinal cell degeneration. It is, however, 79 believed that other, yet unidentified class I myosins, may participate more directly in 80 photoreceptor function. Here we present compelling evidence for another 81 unconventional actin-based motor protein, MYO1C, with its primary localization to 82 photoreceptors, that plays a role in retinal cell structure and function via opsins 83 trafficking to the photoreceptor OS. 84 Rhodopsin and cone pigments in photoreceptor OS mediate scotopic and 85 photopic vision, respectively. They consist of opsin, the apo-protein, and 11-cis retinal, a 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.02.129890; this version posted June 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 86 vitamin A-based chromophore. Light absorption by 11-cis retinal triggers a 87 conformational change in opsin [8]. This, in turn, initiates a G protein-coupled receptor 88 (GPCR) signaling pathway/phototransduction cascade, signaling the presence of light. 89 Thus, the presence of opsins in the photoreceptor OS is critical for vision [1-9]. Each 90 photoreceptor cell contains an OS housing the phototransduction machinery, an inner 91 segment (IS) where proteins are biosynthesized and energy is being produced, and a 92 synaptic terminal for signal transmission. One of the most fundamental steps in vision is 93 the proper assembly of signal-transducing membranes, including the transport and 94 sorting of protein components. A major cause of neurodegenerative and other inherited 95 retinal disorders is the improper localization of proteins. Mislocalization of the dim-light 96 photoreceptor protein rhodopsin is a phenotype observed in many forms of the blinding 97 disease, including retinitis pigmentosa. The proteins that participate in 98 phototransduction (including rhodopsin, transducin, phosphodiesterase [PDE6], or the 99 cyclic nucleotide gated channels [CNG], are synthesized in the IS and must be 100 transported through the connecting cilium (CC) to the OS. These proteins are either 101 transmembrane (TM) proteins or peripherally associated membrane proteins that are 102 attached to the membrane surface [1-9]. How the TM proteins (e.g., rhodopsin and 103 CNG) and peripherally associated proteins (e.g., transducin and PDE6) traffic through 104 the IS to incorporate eventually in the nascent disc membrane or the photoreceptor 105 outer membrane is not fully understood and constitutes an area of intense research, as 106 improper trafficking of these protein causes retinal cell degeneration and can lead to 107 blindness [1-9]. 4 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.02.129890; this version posted June 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 108 Genetic mutations in myosins that lead to hearing loss have also been 109 associated with retinal degeneration. Some of the essential genes known to be involved 110 in either or both of these functions belong to a family of unconventional motor proteins 111 and include MYO3A [15], MYO7A , MYO6 , MYO15 [16], and MYO5. A recent report 112 identified another unconventional myosin associated with deafness, MYO1C, where 113 mutations which affects its nucleotide-binding pocket and calcium binding ability [17]. 114 Importantly, MYO1C was identified in the proteomic analysis of the retina and vitreous 115 fluid as part of a protein hub involved in oxidative stress [18-20]. MYO1C is an actin- 116 binding motor protein that is widely expressed in multiple cell types. It has been shown 117 to participate in a variety of cellular functions including protein trafficking and 118 translocation [12, 21-23]. As MYO1C has low tissue specificity based on mRNA and 119 protein expression, it remains unclear which cell type is most dependent on MYO1C 120 trafficking function and is affected by the loss of MYO1C. 121 In this study, we aimed to systematically analyze the function of the motor protein 122 MYO1C in protein trafficking in photoreceptors. Here, we find that a global genetic 123 deletion of Myo1c results in progressive mistrafficking of opsins to the OS. Using retinal 124 lysate from wild-type (WT) mice in co-immunoprecipitation assays, we show that 125 MYO1C and rhodopsin directly interact, indicating that opsin is a cargo for MYO1C. 126 Loss of MYO1C promoted a progressive OS degeneration concomitant with a reduction 127 in rod and cone photoreceptor cell function, suggesting that MYO1C is critical for retinal 128 structure and function. Our findings have significant clinical implications for 129 degenerative rod and cone diseases, as mutations in MYO1C or its interacting partners 5 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.02.129890; this version posted June 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
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