FYCO1 and autophagy control the integrity of the haploid male germ cell-specific RNP granules

Abstract

Ribonucleoprotein (RNP) granules play a major role in compartmentalizing cytoplasmic RNA regulation. Haploid round spermatids that have exceptionally diverse transcriptomes are characterized by a unique germ cell-specific RNP granule, the chromatoid body (CB). The CB shares many characteristics with somatic RNP granules but also has germline-specific features. The CB appears to be a central structure in PIWI-interacting RNA (piRNA)-targeted RNA regulation. Here, we identified a novel CB component, FYCO1, which is involved in the intracellular transport of autophagic vesicles in somatic cells. We demonstrated that the CB is associated with autophagic activity. Induction of autophagy leads to the recruitment of lysosomal vesicles onto the CB in a FYCO1-dependent manner as demonstrated by the analysis of a germ cell-specific Fyco1 conditional knockout mouse model. Furthermore, in the absence of FYCO1, the integrity of the CB was affected and the CB was fragmented. Our results suggest that RNP granule homeostasis is regulated by FYCO1-mediated autophagy.

Germ granule-mediated RNA regulation in male germ cells

“…Autophagy could, for example, be involved in the assembly and clearance of the CB material in an analogous way that has been demonstrated for stress granules that are stress-responsive somatic RNP granules (Buchan et al 2013, Ryu et al 2014, Seguin et al 2014. Interestingly, a CB component FYCO1 (FYVE and coiled-coil domain-containing protein 1) was shown to be responsible for the recruitment of autophagosomes and lysosomes onto the CB (Da Ros et al 2017). FYCO1 binds phosphatidylinositol 3-phosphate (PtdIns3P) and MAP1LC3B/LC3B (microtubule-associated proteins 1A/1B light chain 3B) that is anchored on the autophagosomal membrane (Pankiv et al 2010.…”

“…A doublemembrane structure, the autophagosome, forms to sequester a part of the cytosol that subsequently fuses with a lysosome. The vesicles associated with the CB contain autophagosomal and lysosomal markers, and the induction of autophagy leads to the dramatic increase in the accumulation of lysosomes onto the CB (Da Ros et al 2017). Therefore, autophagy seems to provide additional catabolic activity for the CB-dependent processes.…”

“…The movement of the CB has been shown to be microtubule dependent and can be disturbed by microtubule-depolymerizing drugs, which also cause CB fragmentation (Ventela et al 2003, Da Ros et al 2017. One possible link between the microtubules and the CB could be the microtubule-binding kinesin motor protein, KIF17b, which accumulates in the CB (Kotaja et al 2006).…”

“…The abundance of vesicles associated with the CB is even more prominent in elongating spermatids where the late CB is completely covered with vesicles (Fujii et al 2016). Recently, these CB-associated vesicles were shown to be involved in the autophagy-lysosomal pathway (Fujii et al 2016, Da Ros et al 2017. Autophagy ('to eat oneself' from Greek) is a conserved mechanism where various macromolecules and organelles are delivered to lysosomes for degradation (Mizushima & Komatsu 2011).…”

Contribution of Autophagy to the Physiological and Pathophysiological Functions in the Mammalian Testis

“…The accessary material from the CB is finally discarded together with the rest of the cytoplasm in the residual body. It is demonstrated that the clearance of these materials is mainly undertook by autophagy via an FYCO1-dependent pathway, and the induction of autophagy enables the homeostasis of CB [34]. Mechanistically, FYCO1 functions as a docking site for LC3 and LAMP1-positive membranes mediating the recruitment of autophagosome and lysosome to the CB.…”