Agnoprotein Is an Essential Egress Factor during BK Polyomavirus Infection

Abstract

BK polyomavirus (BKPyV; hereafter referred to as BK) causes a lifelong chronic infection and is associated with debilitating disease in kidney transplant recipients. Despite its importance, aspects of the virus life cycle remain poorly understood. In addition to the structural proteins, the late region of the BK genome encodes for an auxiliary protein called agnoprotein. Studies on other polyomavirus agnoproteins have suggested that the protein may contribute to virion infectivity. Here, we demonstrate an essential role for agnoprotein in BK virus release. Viruses lacking agnoprotein fail to release from host cells and do not propagate to wild-type levels. Despite this, agnoprotein is not essential for virion infectivity or morphogenesis. Instead, agnoprotein expression correlates with nuclear egress of BK virions. We demonstrate that the agnoprotein binding partner α-soluble N-ethylmaleimide sensitive fusion (NSF) attachment protein (α-SNAP) is necessary for BK virion release, and siRNA knockdown of α-SNAP prevents nuclear release of wild-type BK virions. These data highlight a novel role for agnoprotein and begin to reveal the mechanism by which polyomaviruses leave an infected cell.

Expression of novel proteins by polyomaviruses and recent advances in the structural and functional features of agnoprotein of JC virus, BK virus, and simian virus 40

“…JCV Asp38 is substituted for Glu and Gln for BKV and SV40 agnoproteins, respectively, at the same position , viral transcription, functioning as a viroporin (Suzuki et al, 2013(Suzuki et al, , 2010, virion formation (Sariyer et al, 2006;Suzuki et al, 2012). BKV Agno has also been implicated in interfering with exocytosis (Johannessen et al, 2011), inhibition of the viral DNA replication (Gerits et al, 2015) and egress of virions from the infected cells (Panou et al, 2018). In addition, JCV Agno was shown to deregulate cell cycle progression (Darbinyan et al, 2002).…”

Intercellular Transmission of Naked Viruses through Extracellular Vesicles: Focus on Polyomaviruses

“…Interestingly, immediately upstream of the VP1 gene of SV40, BKPyV, and JCPyV polyomaviruses resides a gene referred to as agnogene that encodes for an approximately 70 amino acid (aa) long Agnoprotein [ 41 ]. Even though the precise role of the Agnoprotein remains unclear, it seems to be involved in virus egress [ 42 ], and a viroporin activity was described [ 43 ]. We hypothesized that the Agnoprotein could play a role in EV-associated polyomavirus egress.…”

BK virus: Current understanding of pathogenicity and clinical disease in transplantation

“…The VP2 and VP3 minor capsid proteins are located on the internal surface of the capsid, with one molecule of VP2 or VP3 associated with each VP1 pentamer . Whilst expressed late in infection, the agnoprotein does not form a structural component of the virus capsid, but rather serves to aid in release of infectious progeny virus from the infected cell …”

“…Late gene transcription ensues and progeny virions are formed within the nucleus once capsid proteins assemble around the newly synthesized genomes . These virions are then released from the infected cell by an incompletely understood mechanism, which may require active secretion of virions rather than passive lysis of the infected cell …”