Summary auto-generated
HIV-1 encodes three proteins that reduce CD4 cell surface levels, with Vpu and Env acting cooperatively to accelerate CD4 degradation. This study investigated whether the proteasome pathway mediates Vpu/Env-induced CD4 degradation using human HeLa cells expressing HIV-1 proteins. Researchers treated cells with proteasome inhibitors (lactacystin, ALLN, ALLM) and non-proteasome protease inhibitors (TLCK, TPCK, E64) and measured CD4 levels via flow cytometry and pulse-chase analysis. Proteasome inhibitors blocked the rapid degradation of CD4 in a dose-dependent manner, while non-proteasome inhibitors had no effect. CD4 half-life increased from approximately 1 hour to over 3 hours when proteasome inhibitors were present. Notably, Vpu contains a diserine motif identical to one found in IκB, a known proteasome-degraded protein, suggesting HIV-1 may have acquired this cellular degradation signal. The findings indicate that HIV-1 Vpu and Env exploit the host proteasome pathway to downregulate CD4, potentially by delivering a ubiquitin-proteasome recognition signal.
Key findings
- Proteasome inhibitors lactacystin, ALLN, and ALLM block Vpu/Env-induced rapid CD4 degradation in a dose-dependent manner
- Non-proteasome protease inhibitors (TLCK, TPCK, E64) do not affect CD4 degradation, indicating specificity to the proteasome pathway
- CD4 half-life increases from ~1 hour to >3 hours in the presence of proteasome inhibitors in cells expressing HIV Vpu and Env
- Vpu contains a diserine motif (DSGNES) homologous to the proteasome degradation signal in IκB, suggesting possible horizontal gene transfer from cellular sequences
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Abstract
Human immunodeficiency virus (HIV) type 1 encodes three genes, Vpu, Env and Nef, that decrease cellular CD4. Vpu and Env act cooperatively to accelerate degradation of CD4 in the endoplasmic reticulum. Here we report that Vpu/Env-induced CD4 degradation is inhibited by lactacystin, a specific inhibitor of the proteasome, and by other proteasome inhibitors, but not by non-proteasome protease inhibitors. We also note that Vpu has amino acid sequence homology with a segment of IkappaB known to be involved in proteasome-mediated degradation, suggesting that HIV-1 could have transduced cellular sequences to enhance down-regulation of CD4.