title: Identification and characterization of naturally occurring splice variants of SAMHD1.
abstract: BACKGROUND
  Sterile Alpha Motif and HD domain-containing protein 1 (SAMHD1) is a recently identified host factor that restricts HIV-1 replication in dendritic and myeloid cells. SAMHD1 is a dNTPase that presumably reduces the cellular dNTP levels to levels too low for retroviral reverse transcription to occur. However, HIV-2 and SIV encoded Vpx counteracts the antiviral effects of SAMHD1 by targeting the protein for proteasomal degradation. SAMHD1 is encoded by a multiply spliced mRNA and consists of 16 coding exons.
  
  
  RESULTS
  Here, we identified two naturally occurring splice variants lacking exons 8-9 and 14, respectively. Like wildtype SAMHD1, both splice variants localize primarily to the nucleus, interact with Vpx, and retain some sensitivity to Vpx-dependent degradation. However, the splice variants differ from full-length SAMHD1 in their metabolic stability and catalytic activity. While full-length SAMHD1 is metabolically stable in uninfected cells, both splice variants were inherently metabolically unstable and were rapidly degraded even in the absence of Vpx. Vpx strongly increased the rate of degradation of full-length SAMHD1 and further accelerated the degradation of the splice variants. However, the effect of Vpx on the splice variants was more modest due to the inherent instability of these proteins. Analysis of dNTPase activity indicates that neither splice variant is catalytically active.
  
  
  CONCLUSIONS
  The identification of SAMHD1 splice variants exposes a potential regulatory mechanism that could enable the cell to control its dNTPase activity on a post-transcriptional level.
authors.affiliation: Viral Biochemistry Section, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Building 4, Room 310; 4 Center Drive, MSC 0460, Bethesda, MD, 20892-0460, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Welbourn
authors.forename: Eri
authors.initials: E
authors.lastname: Miyagi
authors.forename: Tommy E
authors.initials: TE
authors.lastname: White
authors.forename: Felipe
authors.initials: F
authors.lastname: Diaz-Griffero
authors.forename: Klaus
authors.initials: K
authors.lastname: Strebel
mesh_terms: D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D005091:Exons; D014644:Genetic Variation; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism*; D008958:Models, Molecular; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D055550:Protein Stability; D000076106:SAM Domain and HD Domain-Containing Protein 1
chemical_list: D007527:Isoenzymes; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins