Autophagy and ubiquitin–proteasome system contribute to sperm mitophagy after mammalian fertilization
Sunday, 2016/09/11 | 06:16:27
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Won-Hee Song, Young-Joo Yi, Miriam Sutovsky, Stuart Meyers, and Peter Sutovsky SignificanceMaternal inheritance of mitochondria and mitochondrial genes is a major developmental paradigm in mammals. Propagation of paternal, sperm-contributed mitochondrial genes, resulting in heteroplasmy, is seldom observed in mammals, due to postfertilization targeting and degradation of sperm mitochondria, referred to as “sperm mitophagy.” Our and others’ recent results suggest that postfertilization sperm mitophagy is mediated by the ubiquitin–proteasome system, the major protein-turnover pathway that degrades proteins and the autophagic pathway. Here we demonstrate that the co-inhibition of the ubiquitin-binding autophagy receptors, sequestosome 1 (SQSTM1) and gamma-aminobutyric acid receptor-associated protein (GABARAP), and the ubiquitinated protein dislocase valosin-containing protein (VCP)-dependent pathways delayed postfertilization sperm mitophagy. Our findings provide the mechanisms guiding sperm mitochondrion recognition and disposal during preimplantation embryo development, which prevents a potentially detrimental effect of heteroplasmy. AbstractMaternal inheritance of mitochondria and mtDNA is a universal principle in human and animal development, guided by selective ubiquitin-dependent degradation of the sperm-borne mitochondria after fertilization. However, it is not clear how the 26S proteasome, the ubiquitin-dependent protease that is only capable of degrading one protein molecule at a time, can dispose of a whole sperm mitochondrial sheath. We hypothesized that the canonical ubiquitin-like autophagy receptors [sequestosome 1 (SQSTM1), microtubule-associated protein 1 light chain 3 (LC3), gamma-aminobutyric acid receptor-associated protein (GABARAP)] and the nontraditional mitophagy pathways involving ubiquitin-proteasome system and the ubiquitin-binding protein dislocase, valosin-containing protein (VCP), may act in concert during mammalian sperm mitophagy. We found that the SQSTM1, but not GABARAP or LC3, associated with sperm mitochondria after fertilization in pig and rhesus monkey zygotes. Three sperm mitochondrial proteins copurified with the recombinant, ubiquitin-associated domain of SQSTM1. The accumulation of GABARAP-containing protein aggregates was observed in the vicinity of sperm mitochondrial sheaths in the zygotes and increased in the embryos treated with proteasomal inhibitor MG132, in which intact sperm mitochondrial sheaths were observed. Pharmacological inhibition of VCP significantly delayed the process of sperm mitophagy and completely prevented it when combined with microinjection of autophagy-targeting antibodies specific to SQSTM1 and/or GABARAP. Sperm mitophagy in higher mammals thus relies on a combined action of SQSTM1-dependent autophagy and VCP-mediated dislocation and presentation of ubiquitinated sperm mitochondrial proteins to the 26S proteasome, explaining how the whole sperm mitochondria are degraded inside the fertilized mammalian oocytes by a protein recycling system involved in degradation of single protein molecules.
See: http://www.pnas.org/content/113/36/E5261.abstract.html?etoc
PNAS September 6 2016; vol.113; no.36: E5261–E5270
Fig. 1. Putative pathways participating in the elimination of sperm mitochondria by coordinated activities of autophagy and the ubiquitin–proteasome system. (i) The ubiquitin-binding autophagy receptor SQSTM1 could recognize ubiquitinated mitochondrial protein cargo and interact with autophagosome-binding ubiquitin-like modifiers, such as LC3 and/or GABARAP to transport them toward autophagosome. (ii) Ubiquitinated proteins could be extracted from mitochondria and form aggresomes, the protein aggregates induced by ubiquitin-binding adaptor protein HDAC6 that transports them along the microtubules to the autophagophore. (iii) Protein dislocase VCP could extract and present the ubiquitinated mitochondrial membrane proteins to the 26S proteasome. |
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