Molecular and Cellular Immunology (Heissmeyer)

Project description

The Roquin and Regnase family of RNA-binding proteins shape the adaptive immune response by playing an important role in T cells, where they bind and repress proinflammatory target mRNAs. Our most recent data demonstrate that Roquin-1 and Regnase-1 proteins can interact and form a ternary complex on RNA, thereby acquiring enhanced post-transcriptional potential. Upon T cell receptor (TCR) signaling, the MALT1 paracaspase is activated and cleaves Roquin and Regnase proteins. Cleavage of these RNA-binding proteins derepresses expression of their target mRNAs that specify differentiation and effector functions. Our published and preliminary data suggest that this signaling axis controls Th17 differentiation and anti-fungal effector functions.

While Roquin proteins have been almost extensively studied in T cells, little is known about their physiologic importance in myeloid cells. Nevertheless, myeloid cells have C-type lectin receptors that can be activated by fungal or mycobacterial components leading to intracellular signal transduction that similarly activates the MALT1 paracaspase. This signal transduction in myeloid cells was shown to be important for the production of cytokines that induce Th1 and Th17 responses.

In the proposed project we will investigate the expression of Roquin and Regnase proteins as well as their signal-induced inactivation in macrophages. We will determine Roquin bound target mRNAs and find out how they are regulated by altered stability or altered translation efficiency in response to MALT1 signaling induced by C-type lectin receptors. Finally, we will characterize immediate cytokine responses and cellular phenotypes in mice vaccinated with Bacillus Calmette-Guerin (BCG), a potent stimulator of Mincle-induced activation of macrophages.