BK channels regulate extracellular Tat-mediated HIV-1 LTR transactivation

Area of Science:

• Cell Biology
• Virology
• Neuroscience

Background:

• HIV-1 Tat protein is crucial for viral replication and pathogenesis.
• Exogenous Tat enters cells via endocytosis and must escape endolysosomal degradation to reach the nucleus.
• Endolysosomal pH influences Tat degradation and subsequent HIV-1 LTR transactivation.

Purpose of the Study:

• To investigate the role of TRPML1 and BK channels in regulating endolysosomal pH.
• To determine the effect of TRPML1 and BK channel activation on HIV-1 Tat degradation and LTR transactivation.
• To explore the therapeutic potential of modulating endolysosomal pH for HIV-1 comorbidities.

Main Methods:

• Utilized U87MG cells with stably integrated HIV-1 LTR luciferase reporter.
• Activated TRPML1 channels using ML-SA1.
• Assessed endolysosomal pH, Tat degradation, and HIV-1 LTR transactivation.
• Employed pharmacological inhibitors and shRNA to study BK channel involvement.

Main Results:

• ML-SA1-induced TRPML1 activation acidified endolysosomes, restricting Tat-mediated HIV-1 LTR transactivation.
• TRPML1 channel activation effects on LTR transactivation were dependent on BK channel activity.
• Activation of TRPML1 and BK channels enhanced cellular degradation of exogenous Tat.

Conclusions:

• Acidifying endolysosomes via TRPML1 and BK channel activation promotes exogenous Tat degradation.
• Modulating endolysosomal pH presents a potential therapeutic strategy for latent HIV-1 infection and associated neurological conditions.