Hantavirus Pulmonary Syndrome-Associated Hantaviruses Contain Conserved and Functional ITAM Signaling Elements

Abstract

Hantaviruses infect human endothelial and immune cells, causing two human diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). We have identified key signaling elements termed immunoreceptor tyrosine-based activation motifs (ITAMs) within the G1 cytoplasmic tail of all HPS-causing hantaviruses. ITAMs direct receptor signaling within immune and endothelial cells and the presence of ITAMs in all HPS-causing hantaviruses provides a means for altering normal cellular responses which maintain vascular integrity. The NY-1 G1 ITAM was shown to coprecipitate a complex of phosphoproteins from cells, and the G1 ITAM is a substrate for the Src family kinase Fyn. The hantavirus ITAM coprecipitated Lyn, Syk, and ZAP-70 kinases from T or B cells, while mutagenesis of the ITAM abolished these interactions. In addition, G1 ITAM tyrosines directed intracellular interactions with Syk by mammalian two-hybrid analysis. These findings demonstrate that G1 ITAMs bind key cellular kinases that regulate immune and endothelial cell functions. There is currently no means for establishing the role of the G1 ITAM in hantavirus pathogenesis. However, the conservation of G1 ITAMs in all HPS-causing hantaviruses and the role of these signaling elements in immune and endothelial cells suggest that functional G1 ITAMs are likely to dysregulate normal immune and endothelial cell responses and contribute to hantavirus pathogenesis.

Regulatory T cell-like responses in deer mice persistently infected with Sin Nombre virus

“…However, hantaviruses are among the simplest of viruses, with only three genes encoding four polypeptides. Although HCPS-causing hantavirus G N polypeptides have some immunoreceptor tyrosinebased activation motif activities (25) and some hantaviruses can impair type I IFN responses in human cells (24) in vitro, no such activities have been demonstrated in vivo in reservoir hosts.…”

“…Of the four polypeptides encoded by hantaviruses, none has been reported to possess such immunomodulating activities in their reservoirs, although some can affect type I IFN responses in human cells (24). In addition, hantaviruses that cause HCPS possess an immunoreceptor tyrosine-based activation motif in the G N (or G 1 ) glycoprotein that may influence immune cells or infected endothelial cells (25). However, it is unknown whether this occurs in infected deer mice.…”

The Hantavirus Glycoprotein G1 Tail Contains Dual CCHC-type Classical Zinc Fingers

“…In nonpathogenic hantaviruses, by contrast, the interferon response is activated (9,11). The G1 tail contains conserved immunoreceptor tyrosine-based activation motifs, which are involved in protein-protein interactions in the cellular immune response to viral infection (12). Further, the G1 tail of pathogenic hantaviruses is ubiquitinated and proteasomally degraded (13), which is thought to regulate the activity of the G1 tail (13), whereas the nonpathogenic hantavirus G1 tail is stable.…”

KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions

“…KARAP/DAP12 transcripts are present in bony fishes, rodents, swine and humans, showing the broad conservation of this signaling component in vertebrates [2, 3, 6, 7]. KARAP/DAP12 expression is detectable in both lymphoid and myeloid cells, where it can associate with several activating immunoreceptors, contributing to several biological functions [8].In this review, we will correlate KARAP/DAP12 broad expression in both hematopoietic and non-hematopoietic tissues with pleiotropic functions of this signaling , protein G1 of hantavirus (sequence indicated corresponds to substrain NY1, but G1 proteinITAM sequences of several other hantavirus substrains' have also been reported) [59]. All the ITAM motifs reported here, except for viral molecules, are derived from human sequences of the indicated proteins.…”