Two proteins, hnRNP F and CAD, were identified to complex at high levels with TTP and BRF1 in a RNA-independent manner. Given its previously established role in mRNA regulatory events we focused our study on hnRNP F and found that it stimulates the degradation of a subset of TTP/BRF1-target mRNAs. Stimulation of TTP/BRF1-target mRNA decay did not correlate with the extent of hnRNP F mRNA binding, indicating a more complex mechanism than simple concentration-dependent recruitment. Taken together, our observations identify a new component of TTP/BRF-complexes, which serves as a co-factor in a subset of TTP/BRF-mediated decay events. The specific mechanism by which hnRNP F stimulates TTP/ BRF1-mediated decay, and how it interfaces with other TTP/ BRF co-factors, is an important question for future study. Given that hnRNP F is a sequence-specific member of the hnRNP class of RNA-binding proteins that are abundant components of mRNPs, an interesting possibility is that TTP/BRF mRNA-target specificity is dictated in part by the hnRNP composition of the mRNP. If true, this could help explain why TTP/BRF proteins act on only a subset of ARE-containing mRNAs. Our observations showed no correlation between the ability of hnRNP F to stimulate ARE-mRNA decay and the number of predicted hnRNP F binding sites or the extent of hnRNP F mRNA binding. Thus, the mechanism by which hnRNP F stimulates TTP/BRF-mediated degradation is likely more complex, and could depend for example on the position of hnRNP F binding within the mRNA or other aspects of mRNP structure or composition. Future studies should reveal whether the position of hnRNP F binding relative to the ARE or other mRNA BYL719 elements is important, or whether additional mRNP components facilitate the communication between hnRNP F and TTP/BRF proteins. Given that the hnRNP F-TTP/BRF complex is resistant to RNase, it is also possible that hnRNP F stimulates TTP/BRF proteins through mechanisms that do not require direct RNA binding by hnRNP F. hnRNP F could stimulate TTP/BRF activity as part of the TTP/BRF complex for example by affecting the ability of TTP/BRF proteins to recruit mRNA decay factors, to remodel the mRNP in preparation for mRNA degradation, or by influencing TTP/BRF regulation by phosphorylation. We observed a consistent – albeit moderate – reduction in the fraction of cellular TTP that complexes with hnRNP F over time of stimulation of RAW macrophages with LPS. Given that TTP is regulated by phosphorylation and dephosphorylation events during a time course of LPS stimulation, this reduction in hnRNP F association with TTP could signify that the interaction is modulated by phosphorylation. Alternatively, the dramatic increase in TTP levels that occurs during LPS stimulation could render the cellular levels of hnRNP F limiting for the interaction. The remodeling of mRNPs that takes place to allow mRNA degradation is generally associated with repression of translation initiation and hnRNP F has previously been implicated in translational repression ; thus, an important question for future study is whether this activity of hnRNP F plays a role in TTP/BRF-mediated degradation of ARE-mRNAs.