Controlling clots with Clk1

NF-κB, a central proinflammatory regulator, gets activated by TNF receptor–associated factors (TRAFs). But He et al. (page 2413) now report that one TRAF family member (TRAF3) instead negatively regulates an alternative NF-κB activation pathway. Classical activation of NF-κB occurs by TRAF-controlled degradation of cytoplasmic inhibitory binding proteins, which leads to nuclear accumulation of the p50 forms of NF-κB. Activation can also occur by a recently discovered route requiring NF-κB–inducing kinase (NIK), which releases a different NF-κB complex, thus one containing p52. It was known that, unlike other TRAFs, overexpression of TRAF3 does not induce the classical NF-κB pathway. By examining TRAF3-null mice (which die soon after birth), He et al. now show that cells from these mice have constitutively active noncanonical p52 NF-κB. This constitutive activation was associated with aberrant accumulation of NIK protein, but not mRNA, suggesting that TRAF3 blocks noncanonical NF-κB by reducing NIK protein stability. Crossing the TRAF3 −/− mice with mice that lacked p52 prevented their early death, showing that overactivity of p52 was, indeed, the cause of lethality. The final cause of death in TRAF3 −/− mice is uncertain but is most likely due to over-inflammation caused by the unfettered activation of NF-κB-signaling. Platelets are critical blood cells involved in clotting. An early step in clot construction requires tissue factor (TF), but whether platelets make TF was unknown. New work by Schwertz et al. (page 2433) reveals that these nuclei-free cells doproduce TF by cytoplasmic splicing and further identify the kinase Clk1 as a splicing activator. After injury to a blood vessel, platelets are the first cells on the scene to plug the hole. Platelets get activated by attachment to exposed collagen (amongst other things), and promote a TF-dependent coagulation cascade on their cell membranes. This ultimately results in large-scale fibrin production and the assembly of a tough fibrin meshwork over the platelet plug. TF is released from the injured tissue, but whether platelets themselves express TF is a debated question. Schwertz et al. found that activated human platelets contained TF mRNA. Resting platelets instead contained unspliced TF pre-mRNA. Activation, the team showed, induced splicing and subsequent translation of TF in as little as 5 min. Cytoplasmic splicing was described for the first time by this group a year ago. The precise mechanism is unknown, but splicing factor SF2/ASF was identified in platelet cytoplasms. In nucleated cells, Clk1 activates SF2/ASF by phosphorylation. Interrupting this modification, …