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Role of CEP112 and hnRNPA2B1 complex phase separation in RNA granule translation during spermiogenesis in humans and mice

ABSTRACT: Centrosomal proteins (CEPs) are active components of centrioles that mediate multiple biological processes, such as ciliogenesis and centriole biogenesis; therefore, CEP dysfunctions are broadly implicated in various human diseases. Although CEPs have been genetically linked to reproduction, the underlying molecular mechanisms remain poorly understood. Here, we report that knocking out Cep112 in mice causes male infertility with various sperm abnormalities and phenotypes consistent with human asthenoteratozoospermia. Microscopic observations revealed CEP112 is a novel component of atypical centrioles in human sperm cells. Mechanically, as an intrinsically disordered region-rich RNA-binding protein, CEP112 interacted with hnRNPA2B1 and condensed with key spermiogenesis-related mRNA molecules (Fsip2, Cfap61, and Cfap74) via liquid–liquid phase separation, which promoted RNA transport and the maintenance of local translation during spermiogenesis. Furthermore, two patients with bi-allelic variants in CEP112 were identified in a cohort of 568 unrelated infertile men, and in vitro experiments showed the mutations affected the phase-separation characteristics. Our findings provide new information on the roles of CEP112 and LLPS in male reproductive biology.

INSTRUMENT(S): ultraflex

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Testis

SUBMITTER: Xueguang Zhang

LAB HEAD: Xueguang Zhang

PROVIDER: PXD037982 | Pride | 2024-09-05

REPOSITORIES: Pride

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			Action	DRS
	CEP112_2_Slot1-13_1_10029.d.zip	Other
	CEP112_3_Slot1-13_1_10030.d.zip	Other
	SA100LQR1_CEP112_Slot1-5_1_9347.d.zip	Other
	SA100LQR1_WT_Slot1-4_1_9345.d.zip	Other
	WT_2_Slot1-12_1_10026.d.zip	Other

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Role of CEP112 and hnRNPA2B1 complex phase separation in RNA granule translation during spermiogenesis in humans and mice

Project description:Centrosomal proteins (CEPs) are active components of centrioles that mediate multiple biological processes, such as ciliogenesis and centriole biogenesis; therefore, CEP dysfunctions are broadly implicated in various human diseases. Although CEPs have been genetically linked to reproduction, the underlying molecular mechanisms remain poorly understood. Here, we report that knocking out Cep112 in mice causes male infertility with various sperm abnormalities and phenotypes consistent with human asthenoteratozoospermia. Microscopic observations revealed CEP112 is a novel component of atypical centrioles in human sperm cells. Mechanically, as an intrinsically disordered region-rich RNA-binding protein, CEP112 interacted with hnRNPA2B1 and condensed with key spermiogenesis-related mRNA molecules (Fsip2, Cfap61, and Cfap74) via liquid–liquid phase separation, which promoted RNA transport and the maintenance of local translation during spermiogenesis. Furthermore, two patients with bi-allelic variants in CEP112 were identified in a cohort of 568 unrelated infertile men, and in vitro experiments showed the mutations affected the phase-separation characteristics. Our findings provide new information on the roles of CEP112 and LLPS in male reproductive biology. 4 samples

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