The tyrosine-based YXXØ targeting motif of murine leukemia virus envelope glycoprotein affects pathogenesis

Area of Science:

• Virology
• Molecular Biology
• Cell Biology

Background:

• Retroviruses, including murine leukemia viruses (MuLV), possess a tyrosine-based motif in their envelope glycoprotein's intracytoplasmic domain.
• This motif is implicated in regulating viral budding and cell surface targeting, potentially acting as an endocytosis or localization signal.

Purpose of the Study:

• To investigate the role of the tyrosine-based motif in the envelope glycoprotein of the Cas-Br-E strain of MuLV.
• To determine if this motif functions as an endocytosis signal or a targeting signal for viral budding in polarized cells.

Main Methods:

• Modification of proviral DNA of the ecotropic Cas-Br-E MuLV strain by substituting or deleting the critical tyrosine residue.
• Analysis of viral targeting in polarized Madin-Darby canine kidney (MDCK) epithelial cells.
• Assessment of disease onset and pathology in mice inoculated with wild-type and mutant MuLV.

Main Results:

• Mutant MuLV lacking the critical tyrosine residue lost basolateral targeting in polarized MDCK cells.
• The cell surface expression level of the glycoprotein remained unaffected in mutant viruses.
• Mice inoculated with mutant viruses showed a slight delay in disease onset but exhibited significant pathological changes, including enlarged thymus and lymph nodes.

Conclusions:

• The tyrosine-based motif in MuLV envelope glycoprotein is crucial for basolateral targeting and does not primarily function as an endocytosis signal.
• Disruption of this motif leads to altered viral tropism and distinct pathological outcomes in vivo, suggesting a role in viral pathogenesis beyond simple cell surface expression.