ERManI is required for HIV-1 envelope glycoprotein degradation via endoplasmic reticulum-associated protein degradation pathway [Microbiology]

July 23rd, 2015 by Zhou, T., Frabutt, D. A., Moremen, K. W., Zheng, Y.-H.

Previously, we reported that the mitochondrial translocator protein (TSPO) induces HIV-1 Env degradation via endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway, but the mechanism was not clear. Here, we investigated how the four ER-associated GH47 α-mannosidases ERManI, EDEM1, EDEM2, and EDEM3 are involved in the HIV-1 Env degradation process. Ectopic expression of these α-mannosidases uncovers that only ERManI inhibits HIV-1 Env expression in a dose-dependent manner. In addition, genetic knockout of the ERManI gene MAN1B1 using CRISPR/Cas9 technology disrupts the TSPO-mediated Env degradation. Biochemical studies show that HIV-1 Env interacts with ERManI, and between the ERManI cytoplasmic, transmembrane, lumenal stem, and lumenal catalytic domains, the catalytic domain plays a critical role in the Env-ERManI interaction. In addition, functional studies show that inactivation of the catalytic sites by site-directed mutagenesis disrupts the ERManI activity. These studies identify ERManI as a critical GH47 α-mannosidase in the ERAD pathway that initiates the Env degradation, and suggests that its catalytic domain and enzymatic activity play an important role in this process.
  • Posted in Journal of Biological Chemistry, Publications
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