Staufen-1 Interacts with the Human Endogenous Retrovirus Family HERV-K(HML-2) Rec and Gag Proteins and Increases Virion Production

Abstract

O ver millions of years of coevolution, retroviruses have developed strategies to overcome the tight connection between splicing and nuclear mRNA export to allow translation of introncontaining viral mRNAs and incorporation of full-length primary transcripts into particles in the cytoplasm. To achieve this, simple retroviruses rely on cis-acting sequence regions, known as constitutive export elements (CTEs), that depend entirely on factors encoded by the host cell genome. Complex retroviruses, on the other hand, encode accessory proteins that bind to intron-containing viral transcripts to facilitate their nucleocytoplasmic transport (1). These proteins include the Rev protein of HIV, the Rex protein of human T cell leukemia virus (HTLV), and the Rec protein of the human endogenous retrovirus HERV-K. These proteins bind selectively to intricate stem-loop structures in the terminal 3= region of retroviral transcripts, the so-called responsive elements (REs), and use the host protein Crm-1 to support nuclear exit through the pore complex. In addition to their regulatory roles in nuclear mRNA export, there is evidence that Rev and the other related retroviral proteins facilitate translation of the transported mRNAs by enhancing the association with polysomes and accelerating the encapsidation of viral transcripts (2-4).

Upregulation of Human Endogenous Retrovirus-K Is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension

“…Stau1 is a binding partner for HERV-K capsid protein and when Stau1 is overexpressed there is rapid translation of HERV-K sequences. Stau1 prevents EIF2α mediated stress granule formation, thereby facilitating mRNA translation under conditions of cellular stress 47 . This aberrant feature, impaired stress granule formation and heightened mRNA translation in response to inflammatory stress, was described by our group in PAEC with reduced BMPR2 7 , a key feature of PAH, owing to impaired phosphorylation of the elongation factor EIF2α.…”

Molecular functions of human endogenous retroviruses in health and disease

“…Similarly to those proteins, Rec binds to unspliced or partially spliced viral transcripts and mediates their transfer to the cytoplasm where they escape the cellular splicing machinery and can be translated into retroviral polyprotein [61]. Rec may act via interaction with the host-encoded protein Staufen-1 that facilitates transfer of unspliced transcripts to the cytoplasm [62]. The Rec binding site, termed Rec Responsive Element (RRE), is a highly structured RNA motif within the U3R region of the 3 0 LTR.…”

Development of an antigen-capture ELISA for the detection of the p27-CA protein of HERV-K(HML-2)

“…Using Western blot analysis of cell lysates, this was reported to be 3.3-fold for HIV (ChatelChaix et al, 2007) and up to 20-fold for oriHERV-K113 (Hanke et al, 2013b;Hohn et al, 2014). However, particular stages of the viral life cycle are better examined by quantification of virus released into the supernatant, and the AC-ELISA allows the enhancing effect of Staufen-1 co-transfection on virus particle production to be described more precisely.…”

“…To demonstrate a practical use for the ELISA we decided to quantify more precisely the previously reported 20-fold enhancement of HERV-K(HML-2) particle production by Staufen-1 overexpression (Hanke et al, 2013b;Hohn et al, 2014;Mouland et al, 2000). Transfection of increasing amounts of the Staufen-1 expression vector together with a fixed amount of the oriHERV-K113 full length molecular clone increased levels of p27-CA protein in the supernatant by a factor of up to 30 compared to transfection with the molecular clone alone.…”