Manipulation of the N‐terminal sequence of the Borna disease virus X protein improves its mitochondrial targeting and neuroprotective potential

Abstract

To favor their replication, viruses express proteins that target diverse mammalian cellular pathways. Due to the limited size of many viral genomes, such proteins are endowed with multiple functions, which require targeting to different subcellular compartments. One salient example is the X protein of Borna disease virus, which is expressed both at the mitochondria and in the nucleus. Moreover, we recently demonstrated that mitochondrial X protein is neuroprotective. In this study, we sought to examine the mechanisms whereby the X protein transits between subcellular compartments and to define its localization signals, to enhance its mitochondrial accumulation and thus, potentially, its neuroprotective activity. We transfected plasmids expressing fusion proteins bearing different domains of X fused to enhanced green fluorescent protein (eGFP) and compared their subcellular localization to that of eGFP. We observed that the 5-16 domain of X was responsible for both nuclear export and mitochondrial targeting and identified critical residues for mitochondrial localization. We next took advantage of these findings and constructed mutant X proteins that were targeted only to the mitochondria. Such mutants exhibited enhanced neuroprotective properties in compartmented cultures of neurons grown in microfluidic chambers, thereby confirming the parallel between mitochondrial accumulation of the X protein and its neuroprotective potential.-Ferré C. A., Davezac, N., Thouard, A., Peyrin, J. M., Belenguer, P., Miquel, M.-C., Gonzalez-Dunia, D., Szelechowski, M. Manipulation of the N-terminal sequence of the Borna disease virus X protein improves its mitochondrial targeting and neuroprotective potential.

Assessment of therapeutic window for poly‐arginine‐18D (R18D) in a P7 rat model of perinatal hypoxic‐ischaemic encephalopathy

“…Whilst the exact mechanisms whereby CARPs exert their neuroprotective effects are still being explored, there is increasing evidence that this class of peptides possess properties that can impart multiple potential beneficial effects following acute brain injuries such HIE and stroke. For example, CARPs have the capacity to mitigate excitotoxicity (Edwards et al, ; Edwards, Anderton, Knuckey, & Meloni, ; Meloni et al, ; Meloni, Milani, et al, ), reduce intracellular and mitochondrial calcium influx (Edwards et al, ; ; Marshall et al, ; Meloni, Milani, et al, ; Rigobello, Barzon, Marin, & Bindoli, ), reduce cell surface levels of ion channels (Brittain et al, ; Brustovetsky, Pellman, Yang, Khanna, & Brustovetsky, ; MacDougall, Anderton, Edwards, Knuckey, & Meloni, ; Sinai, Duffy, & Roder, ) and TNF receptors (Fotin‐Mleczek et al, ), assist in maintaining mitochondrial integrity (Birk, Chao, Liu, Soong, & Szeto, ; Cerrato, Pirisinu, Vlachos, & Langel, ; Ferré et al, ; Marshall et al, ; Rigobello et al, ; Szelechowski et al, ; Szeto et al, ; Zhao et al, ), inhibit the activity of the proteasome and matrix metalloproteinases (Anbanandam, Albarado, Tirziu, Simons, & Veeraraghavan, ; Cameron, Appel, Houghten, & Lindberg, ; Fugere, Appel, Houghten, Lindberg, & Day, ; Gaczynska, Osmulski, Gao, Post, & Simons, ; Kacprzak et al, ), reduce lipid peroxidation and oxidative stress and modulate immune responses and activate pro‐survival signalling (Cook et al, ; Yang et al, ).…”

The R18 Polyarginine Peptide Is More Effective Than the TAT-NR2B9c (NA-1) Peptide When Administered 60 Minutes after Permanent Middle Cerebral Artery Occlusion in the Rat

“…Also of interest are recent studies surrounding the arginine-rich Borna disease viral mitochondrial-targeting protein, X. The full-length protein X and X-derived peptide fused to a cell penetrating peptide display neuronal, axonal, and mitochondrial protective properties [ 50 , 51 ].…”

Hippocampal expression of a virus-derived protein impairs memory in mice

“…Indeed, as obligate parasites, viruses have evolved highly specific means to hijack cellular pathways to optimize their replication and survival in their host. Hence, studies of viral interference with cell functions have yielded many discoveries on the cell transcription machinery (4), the IFN response (5), the role of mTOR pathways during tumorigenesis (6), or more recently, mitochondrial-driven neuroprotection (7,8). Thus, away from modeling the core aspects of a given mental illness, the study of neurotropic viruses, whose persistence leads to neurological symptoms, could reveal important insights into neural circuits and their alterations during neuropsychiatric disorders.…”