Autophagy is required for efficient meiosis progression and proper meiotic chromosome segregation in fission yeast

Abstract

Autophagy is a conserved intracellular degradation system, which contributes to development and differentiation of various organisms. Yeast cells undergo meiosis under nitrogen-starved conditions and require autophagy for meiosis initiation. However, the precise roles of autophagy in meiosis remain unclear. Here, we show that autophagy is required for efficient meiosis progression and proper meiotic chromosome segregation in fission yeast. Autophagydefective strains bearing a mutation in the autophagy core factor gene atg1, atg7, or atg14 exhibit deformed nuclear structures during meiosis. These mutant cells require an extracellular nitrogen supply for meiosis progression following their entry into meiosis and show delayed meiosis progression even with a nitrogen supply. In addition, they show frequent chromosome dissociation from the spindle together with spindle overextension, forming extra nuclei. Furthermore, Aurora kinase, which regulates chromosome segregation and spindle elongation, is significantly increased at the centromere and spindle in the mutant cells. Aurora kinase down-regulation eliminated delayed initiation of meiosis I and II, chromosome dissociation, and spindle overextension, indicating that increased Aurora kinase activity may cause these aberrances in the mutant cells. Our findings show a hitherto unrecognized relationship of autophagy with the nuclear structure, regulation of cell cycle progression, and chromosome segregation in meiosis.

Meiotic gatekeeper STRA8 suppresses autophagy by repressing Nr1d1 expression during spermatogenesis in mice

“…Our observation that autophagy is being actively suppressed by STRA8 during meiotic initiation in mouse spermatogenesis is in accordance with a recent study of autophagy in rat spermatogenesis, in which autophagy was found only to be activated during late meiotic spermatocytes but not in spermatogonia and early spermatocytes [19]. This is in line with the finding in yeast, in which autophagy is required for proper meiotic chromosome segregation [51]. Together, our findings suggest that activation of autophagy is specifically prevented by STRA8 during meiotic initiation in mammalian germ cell development.…”

“…In fission yeast ( S . pombe ), however, autophagy is thought to be required for chromosome segregation during meiotic division [51]. Thus, these observations underscore the concept that mechanisms of meiotic initiation could differ in model organisms [2].…”

Regulation of inner nuclear membrane associated protein degradation

“…We have discussed the mechanisms crucial for protein clearance from the nuclear envelope through pathways mediated by INMAD, ERAD and autophagy (ER-phagy and nucleophagy), processes which likely interplay. ER-phagy and nucleophagy are known to be key processes in the initiation of meiosis for the clearance of unwanted proteins in budding and fission yeast [104,105]. Nucleophagy has also been reported in animal cells with mutagenized lamins and cells that have been exposed to specific oncogenic stresses [91,92].…”

Delineation of the SUMO-Modified Proteome Reveals Regulatory Functions Throughout Meiosis

“…Autophagy is particularly important for the initiation of meiosis (Wen et al, 2016), but also functions in nuclear architecture and chromosome segregation (Matsuhara and Yamamoto, 2016). Three autophagy factors were SUMOylated: the ubiquitin-like Atg8 protein that undergoes lipidation via conjugation to phosphatidylethanolamine, its cognate E1 enzyme Atg7, and the dual receptor Cue5, which simultaneously binds ubiquitylated cargo and Atg8 (Supplemental Information Table 3).…”