Novel Mechanisms of Translational Control Linking Inflammation and Thrombosis.

The anatomy of platelets is unique and deceptively simple with a key feature being that platelets circulate without a nucleus. This has led to a common misconception that platelets lack the machinery to produce new proteins. However, over 40 studies from 1966 to 1997 collectively demonstrated and/or inferred that platelets synthesize protein. Recent investigations have not only confirmed these earlier reports but show that platelets possess a sophisticated translational apparatus consisting of template mRNAs, ribosomes, and translation initiation factors, such as eukaryotic initiation factor(eIF)-4E and eIF-2a. Current estimates indicate that platelets retain 4,000–6,000 transcripts and platelet-derived mRNAs are capped and polyadenylated at the 5′ - and 3′-untranslated regions, respectively. Data from our group also demonstrates that platelets contain a pool of precursor mRNAs (premRNAs), uridine-rich small nuclear RNAs, and essential splicing machinery. In response to activation, platelets splice specific pre-mRNAs into mature mRNAs. Published results from our group and others demonstrate that platelets use their splicing and translational machinery to synthesize new proteins. B-cell lymphoma 3 (Bcl-3), cyclooxygenase-1 (COX-1), integrin α_IIbβ₃, interleukin-1β (IL-1β), Na⁺-dependent transporter SVCT2, plasminogen activator inhibitor-1 (PAI-1), and tissue factor (TF) are among the most recently characterized proteins reported to be synthesized by platelets. The synthesis of these proteins is highly regulated and involves numerous checkpoints of control. Synthesis of Bcl-3, for example, is controlled by the mammalian Target of Rapamycin (mTOR), one of the most abundantly expressed proteins in platelets. In contrast, platelets use premRNA splicing pathways to regulate the production of pro-IL-1β protein. Processing of pro-IL-1β into its mature form is dependent on an innate cytosolic molecular complex referred to as the inflammasome. The inflammasome has been described in nucleated cells and consists of nucleotide-binding oligomerization domain (NOD)-like receptors, such as NALP-3, as well as caspase-1. Although not previously-described, recent studies from our group demonstrate that platelets possess a functional inflammasome that regulates pro- IL-1β maturation. Identifying and characterizing gene expression pathways in platelets will be an exciting area of investigation throughout the next decade. Our group is actively searching for new targets and, in addition to the inflammasome, we found that platelets harbor reverse transcriptase (RT) activity. Inhibition of RT activity modulates protein synthesis and differentiation responses in platelets. Gene expression pathways including the inflammasome and RT provide platelets with previously-unrecognized mechanisms for controlling thrombosis and inflammation and may be targets for future therapeutic interventions.