MG-132 interferes with iron cellular homeostasis and counteracts bovine herpesvirus
1 productive infection
Filomena Fiorito1*, Carlo Irace2, Marialuisa Piccolo2, Francesca Paola Nocera1, Rita Santamaria2, Luisa De Martino1
1Department of Veterinary Medicine and Animal Production, 2Department of Pharmacy, University of Naples Federico II, 80137 Naples, Italy.
filomena.fiorito@unina.it
Objectives
Bovine herpesvirus 1 (BoHV-1) may provoke rhinotracheitis, conjunctivitis, abortions and shipping fever in cattle. To efficiently reproduce, BoHV-1 requires an iron-replete cell host. However, bovine cells (MDBK) response to viral infection determines an increase in ferritin levels and a decrease of transferrin receptor 1 (TfR-1) expression, finally lowering labile iron pool extent. Hence, cells could limit iron availability for virus spread [1, 2]. MG-132, a proteasome inhibitor, reduces the efficient BoHV-1 release inhibiting apoptosis and stimulating autophagy [3]. Ferritin, the major iron storage protein in mammalian cells, is proteasome-mediated degradated [4]. Herein, the influence of MG-132 on iron metabolism during BoHV-1 infection was examined. Materials and methods
Cell viability, virus titration and Western blot were carried. Results
At no-cytotoxic level, MG-132 up-regulated cellular levels of ferritin. Following BoHV-1 infection, by maintaining sustained ferritin expression levels, MG-132 diminished cytotoxicity and viral replication. Ferritin accumulation observed after infection, which was almost doubled in the presence of MG-132, might be caused by the inhibition of proteasome-mediated degradation pathway. A concomitant down-regulation of TfR-1 expression has been also observed, which could contribute to limit cellular iron availability.
Conclusions
Inhibition of cellular proteasome pathway could further limit iron availability for virus production. Indeed, the inhibitory effect on virus replication was accompanied by a decreased cell death. Thus, proteasome inhibitor may result in a marked antiviral ferritin-iron accumulation.
References
[1] Maffettone C, De Martino L, Irace C, Santamaria R, Pagnini U, Iovane G, Colonna A. J Cell Biochem. (2008) 104:213-23.
[2] Fiorito F, Irace C, Di Pascale A, Colonna A, Iovane G, Pagnini U, Santamaria R, De Martino L PLoS One (2013) 8:e58845.
[3] Fiorito F, Iovane V, Cantiello A, Marullo A, De Martino L, Iovane G. Sci Rep. (2017) 7:13306. [4] Rudeck M, Volk T, Sitte N, and Grune T (2000) IUBMB Life 49:451-456.
