Since its initial identification in 2000, the enzyme SAMHD1 has been implicated in various human diseases including autoimmune disorders, HIV infection, and cancers. New findings now directly reveal new functions and mechanisms of SAMHD1 specific to viral infections and inflammatory stimuli. The recently published study in PNAS come from a team led by Ohio State University researchers.
“SAMHD1 isn't a molecular 'good guy' or 'bad guy' per se, but there are cases in which blocking its activity might thwart disease progression,” said study senior author Li Wu.
The team silenced the expression of SAMHD1-silenced in human monocytic cells or primary macrophages and then infected them with a virus (Sendai virus or HIV-1) as well as inflammatory stimuli. When compared with control cells, the silenced cells exhibited significantly higher levels of NF-κB activation and type I interferon (IFN-I). NF-κB and IFN-I are important protein drivers of the mammalian immune response. Inversely, reconstitution and expression of SAMHD1 in knockout cells suppressed NF-κB activation and IFN-I induction with a viral infection.
"Lacking this enzyme due to SAMHD1 gene mutations can activate the human immune system and increase inflammation, and now we better understand the fundamental biological process behind that," said Wu.
In investigating the mechanism behind the immune suppression, the team found that SAMHD1 interacts with proteins that regulate NF-κB and IFN-I. This interaction was further validated in primary human monocytes and macrophages, as well as in mutant mice. The team concluded that SAMHD1 functions in down-regulating innate immune responses to viral infections and inflammatory stimuli, adding that SAMHD1 might be a therapeutic target in controlling such responses.
"In a perfect world, SAMHD1 is responsible for balanced regulation of the immune response, but it also could limit HIV or other viral infections and alter the progression and treatment of certain cancers,” explains Wu. “We need good immune responses, obviously, but we don't want overwhelming immune activation."