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Essential Role of CFAP53 in Sperm Flagellum Biogenesis

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Essential Role of CFAP53 in Sperm Flagellum Biogenesis bioRxiv preprint doi: https://doi.org/10.1101/2021.02.04.429673; this version posted February 4, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Essential role of CFAP53 in sperm flagellum biogenesis 2 Bingbing Wu 1,8#, Xiaochen Yu 2,3,4,5,6#, Chao Liu1, Lina Wang9, Tao Huang2,3,4,5,6, Gang 3 Lu2,3,4,5,6,7, Zi-Jiang Chen2,3,4,5,6,7, Wei Li1,8*, Hongbin Liu2,3,4,5,6,7* 4 1 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese 5 Academy of Sciences, Beijing 100101, China 6 2Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 7 Shandong, 250012, China 8 3Key laboratory of Reproductive Endocrinology of the Ministry of Education, Shandong 9 University, Jinan, Shandong, 250012, China 10 4Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, 250012, China 11 5Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 12 250012, China 13 6National Research Center for Assisted Reproductive Technology and Reproductive Genetics, 14 Shandong University, Jinan, Shandong, 250012, China 15 7CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sci-ences, the 16 Chinese University of Hong Kong, Hong Kong 999077, China8College of Life Sciences, 17 University of Chinese Academy of Sciences, Beijing 100049, China 18 9China National Clinical Research Center of Respiratory Diseases; Respiratory Department of 19 Beijing Children’s Hospital, Capital Medical University; National Center for Children’s Health, 20 China 21 # These authors contributed equally to this work. 22 *Corresponding Authors: 23 Dr. Wei Li 24 [email protected] 25 Dr. Hongbin Liu 26 [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.04.429673; this version posted February 4, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 27 Keywords: male infertility, flagellum, CFAP53, intramanchette transport, intraflagellar 28 transport 29 Abstract 30 The sperm flagellum is essential for male fertility. Despite vigorous research progress towards 31 understanding the pathogenesis of flagellum-related diseases, much remains unknown about 32 the mechanisms underlying the flagellum biogenesis itself. Here, we show that the cilia and 33 flagella associated protein 53 (Cfap53) gene is predominantly expressed in testes, and it is 34 essential for sperm flagellum biogenesis. The knockout of this gene resulted in complete 35 infertility in male mice but not in the females. CFAP53 localized to the manchette and sperm 36 tail during spermiogenesis, the knockout of this gene impaired flagellum biogenesis. 37 Furthermore, we identified two manchette and sperm tail-associated proteins that interacted 38 with CFAP53 during spermiogenesis. The disruption of Cfap53 decreased the expression level 39 of these two proteins and disrupted their localization in spermatids. Together, our results 40 suggest that CFAP53 is an essential protein for sperm flagellum biogenesis, and its mutations 41 might be associated with MMAF. 42 43 44 45 46 47 48 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.04.429673; this version posted February 4, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 49 Introduction 50 Infertility is a widespread human health issue, affecting 10%–15% of couples worldwide, and 51 male factors account for around 50% of these cases (Boivin et al., 2007; Tüttelmann et al., 52 2018). Male infertility is clinically diagnosed as azoospermia, decreased sperm concentration 53 (oligozoospermia), reduced percentage of morphologically normal sperm (teratozoospermia), 54 or lower sperm motility (asthenozoospermia) (Coutton et al., 2015; Ray et al., 2017; Tüttelmann 55 et al., 2018; Zinaman et al., 2000). Spermatozoa are polarized cells composed of two main parts, 56 the head and the flagellum. The flagellum makes up about 90% of the length of the sperm and 57 is essential for sperm motility (Burgess et al., 2003; Mortimer, 2018), and it contains axoneme 58 and peri-axonemal structures, such as the mitochondrial sheath, outer dense fibers, and the 59 fibrous sheath (Mortimer, 2018), and the presence of these structures allows the flagellum to 60 be divided into the connecting piece, midpiece, principal piece, and endpiece (M. S. Lehti & A. 61 Sironen, 2017). Defects in formation of the flagellum disrupt sperm morphology and motility, 62 leading to male infertility (Chemes & Rawe, 2010; Sironen et al., 2020; Turner et al., 2020). 63 Great progress has been made in our understanding of the pathogenesis of flagella-related 64 diseases in recent years, but the pathogenic genes and mechanisms of flagellum biogenesis are 65 far from being fully understood. 66 The flagellum needs to be integrated with the head in order to function properly during 67 fertilization, and a very complex structure called the sperm head-tail coupling apparatus (HTCA) 68 is necessary for the integration of the sperm head and the flagellum, and defects in this structure 69 result in acephalic spermatozoa syndrome (Wu et al., 2020). Recently, SUN5, PMFBP1, 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.04.429673; this version posted February 4, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 70 HOOK1, BRDT, TSGA10, and CEP112 have been found to be involved in the assembly of the 71 HTCA, and mutations in these genes are associated with acephalic spermatozoa syndrome 72 (Chen et al., 2018; Li et al., 2017; Sha, Wang, et al., 2020; Sha et al., 2018; Shang et al., 2018; 73 Zhu et al., 2018; Zhu et al., 2016). Abnormalities of the axoneme and accessory structures 74 mainly result in asthenozoospermia, which is associated with morphological flagellar defects 75 such as abnormal tails, irregular mitochondrial sheaths, and irregular residual cytoplasm 76 (Escalier & Touré, 2012; Tu et al., 2020). Previous studies have identified several flagella- 77 associated genes, including AKAP3, AKAP4, TTC21A, TTC29, FSIP2, DNAH1, DNAH2, 78 DNAH6, DNAH8, DNAH17, and DZIP1, that are involved in sperm flagellum biogenesis (Ben 79 Khelifa et al., 2014; Y. Li et al., 2019; C. Liu et al., 2019; C. Liu et al., 2020; W. Liu et al., 80 2019; Lv et al., 2020; Martinez et al., 2018; Sha, Wei, et al., 2020; Tu et al., 2019; Turner et al., 81 2001). Mutations in these genes cause multiple morphological abnormalities of the flagella 82 (MMAF), which is characterized as sperm without flagella or with short, coiled, or otherwise 83 irregular flagella (Ben Khelifa et al., 2014; Touré et al., 2020). There are two evolutionarily 84 conserved bidirectional transport platforms that are involved in sperm flagellum biogenesis, 85 including intramanchette transport (IMT) and intraflagellar transport (IFT) (Kierszenbaum, 86 2001, 2002; San Agustin et al., 2015). IMT and IFT share similar cytoskeletal components, 87 namely microtubules and F-actin, that provide tracks for the transport of structural proteins to 88 the developing tail (Abraham L. Kierszenbaum et al., 2011), and mutations in TTC21A, TTC29, 89 SPEF2, and CFAP69, which have been reported to disrupt sperm flagellar protein transport, 90 also lead to MMAF (Dong FN, 2018; C. Liu et al., 2019; Chunyu Liu et al., 2020; W. Liu et al., 91 2019; Sha et al., 2019). 4 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.04.429673; this version posted February 4, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 92 The cilia and flagella associated protein (CFAP) family, such as CFAP58, CFAP61, 93 CFAP69, CFAP65, CFAP43, CFAP44, CFAP70, and CFAP251, is associated with flagellum 94 biogenesis and morphogenesis (Beurois et al., 2019; Dong FN, 2018; He et al., 2020; Huang et 95 al., 2020; W. Li et al., 2019; Li et al., 2020; Tang et al., 2017). Previous studies have indicated 96 that the functional role of CFAP53 (also named the coiled-coil domain containing protein 97 CCDC11) is involved in the biogenesis and motility of motile cilia (Narasimhan et al., 2015; 98 Noël et al., 2016; Perles et al., 2012; Silva et al., 2016), and CFAP53 is localized not only to 99 the base of the nodal cilia, but also along the axoneme of the tracheal cilia (Ide et al., 2020). 100 However, the exact localization and function of CFAP53 during spermiogenesis is still poorly 101 understood. In the present study, we used a Cfap53 knockout mouse model to study the 102 underlying mechanism of CFAP53 in sperm flagellum biogenesis. We demonstrated that 103 CFAP53 is localized to the manchette and the sperm tail of spermatids, and we found that 104 depletion of CFAP53 led to defects in sperm flagellum biogenesis and sperm head shaping. 105 Moreover, we identified two proteins that interacted with CFAP53 during spermiogenesis, 106 namely intraflagellar transport protein 88 (IFT88) and coiled-coil domain containing 42 107 (CCDC42). Cfap53 knockout reduced the accumulation of both IFT88 and CCDC42 and 108 disrupted the localization of IFT88 in spermatids. Thus, in addition to uncovering the essential 109 role of CFAP53 in sperm flagellum biogenesis, we also show that CFAP53 might participate 110 in the biogenesis of the sperm flagellum by collaborating with the IMT and IFT pathways. 111 112 5 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.04.429673; this version posted February 4, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.
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