PMFBP1 was first identified as a polyamine modulating factor 1 binding protein, which could enhance the catabolism and recycling of polyamines 22. SUN5 is a transmembrane protein located in the nuclear envelope (NE), which could interact with the coupling apparatus-related protein DnaJ heat shock protein family (Hsp40) member B13 (DNAJB13) to facilitate SUN5 protein folding in order to ensure the interaction between the implantation fossa and an unknown protein in the HTCA 21.

Mutations in Sad1 and UNC84 domainвЂ“containing 5 ( SUN5) and Polyamine modulated factor 1 binding protein 1 ( PMFBP1) to date account for ~70% of all cases with acephalic spermatozoa syndrome 19, 20. Recently, new biological techniques together with pedigree analysis enable us identify and verify two acephalic spermatozoa syndrome-causing genes 19, 20. As SPATA6 could interact with myosin light-chain polypeptide 6 on the manchettes of elongating spermatids, it might be involved in myosin-based microfilament transport for the assembly of the segmented columns (Scs) and capitulum (Cp) during sperm headвЂ“tail coupling apparatus (HTCA) formation 16. Many mouse models display acephalic spermatozoa phenotype to some extent 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, among which Spata6-null mice are the first to display uniformly 100% acephalic spermatozoa 16. In the past decades, studies show the acephalic spermatozoa syndrome with familial clustering, suggesting that this is a syndrome with a specific genetic origin 4, 5, 6, 7, 8. One of the most extreme forms of teratozoospermia is acephalic spermatozoa syndrome, which is characterized by decapitated flagella, very few intact spermatozoa, and tailless sperm heads in the semen, and it finally leads to severe male infertility 2, 3. Many teratozoospermia have been reported to cause male infertility 1. The structural and functional integrity of human spermatozoa is essential for male fertility, and any defects of the spermatozoa might be associated with severe male infertility. These results demonstrate that CENTLEIN cooperating with SUN5 and PMFBP1 participates in the HTCA assembly and integration of sperm head to the tail, indicating that impairments of CENTLEIN might be associated with acephalic spermatozoa syndrome in humans. We show that lack of Sun5 results in CENTLEIN and PMFBP1 left in the decapitated tail, while disruption of Pmfbp1 results in SUN5 and CENTLEIN left on the detached sperm head. We find that the absence of Centlein sets SUN5 and PMFBP1 apart, the former close to the sperm head and the latter in the decapitated tail.

We demonstrate that CENTLEIN directly interacts with both SUN5 and PMFBP1, two proteins localized in the HTCA and related with acephalic spermatozoa syndrome. Here, we show that CENTLEIN is indispensable for HTCA integrity and function, and that inactivation of CENTLEIN in mice leads to sperm decapitation and male sterility. The sperm head-to-tail coupling apparatus (HTCA) ensures sperm head-tail integrity while defective HTCA causes acephalic spermatozoa, rendering males infertile.

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