Abstract
Prohibitin 2 (PHB2), an inner mitochondrial membrane (IMM) protein, has recently been identified as a novel receptor involved in parkin-mediated mitophagy. In the field of veterinary medicine, the role of PHB2 in parkin-mediated mitophagy was described, for the first time, in urothelial cells of cattle, naturally infected with bovine papillomavirus (BPV). The BPV2 and BPV13 E5 oncoprotein, responsible for abortive infections in urothelial cells, was detected by RT-PCR. Severe ultrastructural abnormalities of the inner mitochondrial membrane were detected using transmission electron microscopy. PHB2 formed a functional complex with PHB1. PHB2 was significantly overexpressed in mitochondrial fractions from urothelial mucosa samples taken from cattle harbouring BPV infection. PHB2 overexpression could be attributed to mitochondrial dysfunction, as its expression levels in the cytosolic, microsomal, and nuclear fractions were seen to be unmodified. Immunoprecipitation studies revealed the interaction between PHB2 and phosphorylated forms of both PINK1 and parkin. Furthermore, PHB2 interacted with LC3-II, a marker of autophagosomal membranes and autophagy receptors, such as p62 and optineurin. PHB2 was shown to interact with transcription factor EB (TFEB), which is activated following parkin-mediated mitophagy, and embryonic stem cell-expressed Ras (ERAS), a constitutive protein coded by ERas. Western blot analysis revealed a significant overexpression of unphosphorylated TFEB in mitochondrial and nuclear fractions from urothelial mucosa samples from cattle suffering from BPV infection. Finally, PHB2 interacted with ERAS, believed to be involved in mitophagosome maturation. Taken together, the molecular and ultrastructural findings of this study suggested that BPV infection is responsible for parkin-dependent mitophagy, in the pathway of which PHB2 plays a crucial role.
Highlights
Mitochondria are double membrane organelles, consisting of an outer mitochondrial membrane (OMM) surrounding an inner mitochondrial membrane (IMM) [1]
We performed virological cattle clinically suffering from chronic enzootic haematuria that have lived free at pasture and grazed investigation to validate our hypothesis that papillomavirus infection, detected bytumours expression on lands rich in bracken fern
Mitochondria are emerging as an essential signalling hub in regulation of both innate and adaptive immunity in eukaryotic cells and are becoming an attractive target for developing new therapies, our knowledge of mitophagy during viral infection is in the initial stage in comparative medicine
Summary
Mitochondria are double membrane organelles, consisting of an outer mitochondrial membrane (OMM) surrounding an inner mitochondrial membrane (IMM) [1]. The sequestration of mitochondria by autophagosomes followed by their degradation in lysosomes, contributes to maintaining the quality of the mitochondrial population, mediating cell survival and viability in response to infection [4,5,6]. Mitophagy has been found to be mediated by protein receptors that interact with LC3 through their LC3-interacting region (LIR). Receptors such as NIX/BNIP3L, BNIP3, and FUNDC1 have been identified as mitophagy receptors in mammalian cells [7]. They comprise prohibitin 2 (PHB2), localised in the IMM [8] and FKBP8, a member of the FK506-binding protein family, anchored in the OMM [9]; both the mitophagy receptors have an LIR
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