HIV Vpr activates a nucleolar-specific ATR pathway to degrade the nucleolar stress sensor CCDC137

Area of Science:

• Virology
• Molecular Biology
• Cell Biology

Background:

• The lentiviral protein Vpr interacts with cellular pathways, leading to host consequences like DNA damage response (DDR) and G2/M arrest.
• The precise mechanisms by which Vpr influences these pathways and affects other cellular processes remain incompletely understood.

Purpose of the Study:

• To investigate how Vpr-induced DDR activation impacts nucleolar processes by examining the Vpr-mediated depletion of the nucleolar protein CCDC137.
• To characterize the role of CCDC137 degradation in Vpr's broader cellular effects.

Main Methods:

• Characterization of CCDC137 as an indirect Vpr target.
• Analysis of CCDC137 degradation in response to Vpr and genomic insults.
• Assessment of nucleolar stress markers, including protein redistribution, morphological changes, and ribosome biogenesis, in the presence of Vpr.
• Investigating the involvement of the ATR pathway in Vpr-induced nucleolar stress.

Main Results:

• CCDC137 is an indirect Vpr target, and its degradation does not correlate with Vpr-induced G2/M arrest.
• CCDC137 degradation is conserved across different lentiviral Vpr proteins and is triggered by genomic insults activating a nucleolar ATR pathway.
• Vpr induces ATR-dependent nucleolar stress, characterized by nucleolar protein redistribution, altered morphology, and repressed ribosome biogenesis, which correlates with CCDC137 degradation.

Conclusions:

• CCDC137 functions as a non-canonical Vpr target and potentially as a sensor of nucleolar disruption.
• Vpr plays a novel role in inducing nucleolar stress, impacting ribosome biogenesis and cellular functions through CCDC137 degradation and ATR pathway activation.