Role of BAG3 in bovine Deltapapillomavirus‐mediated autophagy

Abstract

Bovine Deltapapillomavirus genus (δPV), comprises four members that are highly pathogenic and are frequently associated with bladder tumors of adult cattle and water buffaloes. In particular, bovine δPV‐2 and δPV‐13 are commonly found in urinary bladder tumors in adult large ruminants reared fully or partially on hilly/mountain pasturelands rich in bracken fern (Pteridium spp.) as the urinary bladder of the herbivores is the specific target for bracken genotoxins such as ptaquiloside (PT). PT is a sesquiterpenoid responsible for alkylation of adenine of codon 61 of gene H‐Ras, which results in Glutamine 61 substitution that is essential for guanosine triphosphate (GTP) hydrolysis. Glutamine substitution at position 61 impairs the intrinsic GTPase activity. Therefore, active GTP‐bound conformations (Ras‐GTP) accumulate in cells, thereby causing abnormal cell proliferation and differentiation. The aim of the present study is to stress how bovine δPVs upregulate different forms of selective autophagy, of which BAG3 is a key player. BAG3 plays a central role in autophagy and acts as a multifunctional hub for an interaction network at the cytosolic and mitochondrial level. BAG3 is a functional partner of bovine δPV E5 oncoprotein and forms a complex with molecular chaperones Hsc70/Hsp70/Hsp8B and with cochaperone CHIP. BAG3 interacts with Synpo2. It is believed that this interaction has a crucial role for autophagosome (mitophagosome) formation. Furthermore, in urothelial cells infected by bovine δPVs, BAG3 interacts with parkin and some receptors such as BNIP3/FUNDC1, which suggests that BAG3 is involved in both parkin‐dependent and ‐independent mitophagy that appear upregulate in bladder carcinogenesis of cattle induced by bovine δPVs. Surprisingly, BAG3 interacts also with ERAS, a protein encoded by the ERas gene, a novel member of the RAS family. Unlike in humans, the ERas gene is a functional gene in the cells of adult cattle, and it appears to play a role in bovine BAG3‐mediated selective autophagy, including mitophagy observed in urothelial cells spontaneously infected with bovine papillomavirus.

ERAS Is Constitutively Expressed in the Tissues of Adult Horses and May Be a Key Player in Basal Autophagy

“…Immunoprecipitation demonstrated that in the tissues of adult horses a ternary complex composed of ERAS, the activated form of PDGFβR and AKT, was present. These findings are consistent with those from experimental studies [( 1 ); 22] and strengthen the molecular findings obtained in tissues from adult cattle under both physiological and pathological conditions ( 5 , 6 , 23 ). It is conceivable that ERAS also plays a crucial role in AKT signaling activation via PDGFβR in normal cells of adult horses.…”

Chrysosplenol D can inhibit the growth of prostate cancer by inducing reactive oxygen species and autophagy

“…Autophagy is a process in which eukaryotic cells recycle their own biomacromolecules and organelles through lysosomes 21 . In the process of tumor pathogenesis, autophagy plays a “double‐sided role,” which can not only fight cancer but also promote cancer development 22 .…”

“…Autophagy is a process in which eukaryotic cells recycle their own biomacromolecules and organelles through lysosomes. 21 In the process of tumor pathogenesis, autophagy plays a “double‐sided role,” which can not only fight cancer but also promote cancer development. 22 To explore the regulatory mechanism of autophagy in prostate cancer and develop related drugs for autophagy may provide a new method for the treatment of prostate cancer.…”

SYNPO2 promotes the development of BLCA by upregulating the infiltration of resting mast cells and increasing the resistance to immunotherapy

“…Yet whether SYNPO2 is a tumor suppressor or oncogene remains controversial. Roperto ( 14 ) reported that in bladder cancer infected with Bovineparvovirus (BPV), SYNPO2 upregulates molecular chaperone-mediated mitophagy, promoting cancer cell survival by binding to BAG family molecular chaperone regulator 3 (BAG3), a key autophagy protein. However, other studies have suggested that SYNPO2 may exert tumor-suppressive effects by binding to the 14-3-3 protein via importin-mediated mechanisms ( 9 , 15 ).…”