Three YXXL Sequences of a Bovine Leukemia Virus Transmembrane Protein are Independently Required for Fusion Activity by Controlling Expression on the Cell Membrane.

Ryosuke Matsuura,Hiroyuki Otsuki,Yoko Aida,Naoshi Dohmae,Kazunori Inabe,Kazuo Kurokawa

doi:10.3390/v11121140

Ryosuke Matsuura, Hiroyuki Otsuki + Show 4 more

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https://doi.org/10.3390/v11121140

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Abstract

Bovine leukemia virus (BLV), which is closely related to human T-cell leukemia viruses, is the causative agent of enzootic bovine leukosis, the most common neoplastic disease of cattle. The transmembrane subunit of the BLV envelope glycoprotein, gp30, contains three completely conserved YXXL sequences that fit an endocytic sorting motif. The two N-terminal YXXL sequences are reportedly critical for viral infection. However, their actual function in the viral life cycle remains undetermined. Here, we identified the novel roles of each YXXL sequence. Syncytia formation ability was upregulated by a single mutation of the tyrosine (Tyr) residue in any of the three YXXL sequences, indicating that each YXXL sequence is independently able to regulate the fusion event. The alteration resulted from significantly high expression of gp51 on the cell surface, thereby decreasing the amount of gp51 in early endosomes and further revealing that the three YXXL sequences are independently required for internalization of the envelope (Env) protein, following transport to the cell surface. Moreover, the 2nd and 3rd YXXL sequences contributed to Env protein incorporation into the virion by functionally distinct mechanisms. Our findings provide new insights regarding the three YXXL sequences toward the BLV viral life cycle and for developing new anti-BLV drugs.

Highlights

The immunoreceptor tyrosine-based activation motif (ITAM) is present in the cytoplasmic tails of several protein components of antigen receptors on T and B cells in addition to the Fc receptor for immunoglobulin E [1]
The envelope glycoprotein (Env) of Bovine leukemia virus (BLV), which constitutes the causative agent of enzootic bovine leukosis, the most common neoplastic disease of cattle, and is closely related to human T-cell leukemia viruses (HTLVs), contains two overlapping copies of the (YXXL/I)2 sequence serving as the ITAM at the
We examined the role of the three YXXL sequences in BLV gp30 in the viral life cycle, focusing on the syncytium-forming ability, Env protein distribution, and incorporation of Env protein into the virion, using an infectious molecular clone and Env expression vector (Table 1)

Summary

Introduction

The immunoreceptor tyrosine-based activation motif (ITAM) is present in the cytoplasmic tails of several protein components of antigen receptors on T and B cells in addition to the Fc receptor for immunoglobulin E [1]. This motif is denoted as Yxx(L/I)–x6–8–Yxx(L/I), where x corresponds to a variable residue. Viruses 2019, 11, 1140 humans, and human herpesvirus 8, which can cause sarcomas and primary effusion B cell lymphomas in humans, contain ITAMs in their viral proteins [1,2,3]. The gp and gp proteins form a stable complex through disulfide bonds [8], and are incorporated into budding viral particles [9]. gp binds to cationic amino acid transporter 1

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