HCMV US2 co-opts TRC8 to degrade the endoplasmic reticulum-resident protein LMAN2L

Area of Science:

• Virology
• Immunology
• Cell Biology

Background:

• Human cytomegalovirus (HCMV) protein pUS2 targets host proteins for degradation via the ER-associated degradation (ERAD) pathway.
• HCMV pUS2 degrades major histocompatibility complex class I (MHC-I) to evade immune detection.
• pUS2 also targets other cellular proteins, affecting their cell surface expression.

Purpose of the Study:

• To identify novel cellular targets of HCMV pUS2.
• To investigate the mechanism by which pUS2 affects cell surface protein expression.
• To elucidate the role of LMAN2L in pUS2-mediated protein downregulation.

Main Methods:

• Proteomic plasma membrane profiling was used to identify changes at the cell surface.
• Expression levels of LMAN2L and ITGA6 were analyzed in the presence and absence of pUS2.
• The dependence of LMAN2L degradation on the E3 ligase TRC8 was assessed.

Main Results:

• A novel pUS2 target, lectin mannose binding 2 like (LMAN2L), was identified.
• pUS2-mediated LMAN2L downregulation was dependent on the E3 ligase TRC8.
• LMAN2L deficiency led to the downregulation of integrin alpha-6 (ITGA6) at the cell surface.

Conclusions:

• HCMV pUS2 employs a novel indirect mechanism to downregulate ITGA6 by targeting LMAN2L for degradation.
• This indirect pathway complements pUS2's known direct targeting of other cell surface molecules.
• HCMV utilizes both direct and indirect strategies to modulate host cell surface proteins for immune evasion.