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SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway
Hua Yang1, Pak-Hin Hinson Cheung1, Li Wu1,2
1Department of Microbiology and Immunology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
Abstract:
Sterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) inhibits HIV-1 replication in non-dividing cells by reducing the intracellular dNTP pool. SAMHD1 enhances spontaneous apoptosis in cells, but its effects on HIV-1-induced apoptosis and the underlying mechanisms remain unknown. Here we uncover a new mechanism by which SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells through the mitochondrial pathway. We found that endogenous SAMHD1 enhances apoptosis levels induced by HIV-1 infection in dividing THP-1 cells. Mechanistically, SAMHD1 expression decreases the mitochondrial membrane potential and promotes cytochrome c release induced by HIV-1 infection in THP-1 cells, thereby enhancing mitochondrial apoptotic pathway. SAMHD1-enhanced apoptosis is associated with increased expression of the pro-apoptotic protein BCL-2-interacting killer (BIK) in cells. We further demonstrated that BIK contributes to SAMHD1-enhanced apoptosis during HIV-1 infection. Overall, our results reveal an unappreciated regulatory mechanism of SAMHD1 in enhancing HIV-1-induced apoptosis via the mitochondrial pathway in monocytic cells.
Insights
Sterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) amplifies HIV-1-induced apoptosis in monocytic cells. This occurs via the mitochondrial pathway, involving BCL-2-interacting killer (BIK) protein.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Sterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is known to inhibit HIV-1 replication in non-dividing cells by depleting intracellular deoxynucleotide triphosphate (dNTP) pools.
- While SAMHD1 can induce spontaneous apoptosis, its role in HIV-1-induced apoptosis and the associated mechanisms are not fully understood.
Purpose of the Study:
- To investigate the mechanism by which SAMHD1 influences HIV-1-induced apoptosis in monocytic cells.
- To elucidate the role of the mitochondrial pathway in SAMHD1-mediated apoptosis during HIV-1 infection.
Main Methods:
- Utilized THP-1 monocytic cells to study the effects of endogenous SAMHD1 on HIV-1 infection.
- Assessed apoptosis levels, mitochondrial membrane potential, and cytochrome c release in response to HIV-1 infection and SAMHD1 expression.
- Examined the expression of the pro-apoptotic protein BCL-2-interacting killer (BIK) and its contribution to apoptosis.
Main Results:
- Endogenous SAMHD1 was found to enhance HIV-1-induced apoptosis in dividing THP-1 cells.
- SAMHD1 expression led to decreased mitochondrial membrane potential and increased cytochrome c release, activating the mitochondrial apoptotic pathway during HIV-1 infection.
- SAMHD1-enhanced apoptosis correlated with increased BIK expression, and BIK was demonstrated to be crucial for this effect.
Conclusions:
- SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells through the mitochondrial pathway.
- The pro-apoptotic protein BIK plays a significant role in SAMHD1-mediated apoptosis during HIV-1 infection.
- This study reveals a novel mechanism by which SAMHD1 regulates apoptosis in the context of HIV-1 infection.
