Figure 6
Our working model for biliverdin/BVRA and TLR4 signaling in leukocytes. Biliverdin induced responses are shown in black. Biliverdin acts on BVRA. Our data suggest that biliverdin facilitates formation of BVRA signaling complex(s) that include mTORC2. mTORC2 induces phosphorylation of two targets: PKCζ at Thr410 and Akt at Ser473. PKCζ is involved in LKB1 Ser431 and AMPKα Thr172 phosphorylation. AMPK phosphorylates TSC1/2 at Ser1387 and Raptor at Ser792. Therefore, BVRA activation may contribute to mTORC1 inhibition via two SI: phosphorylated Raptor, which inhibits mTORC1 complex formation, and TSC1/2 mediated inhibition of mTORC1 activity. Because mTORC1 is central to TLR4 signaling in leukocytes10, BVRA inhibition of mTORC1 suppresses TLR4. Pharmacological inhibitors are shown in blue. Torin and PP242, but not rapamycin, inhibited BVRA-mediated protein-protein interactions. TLR4 induced response are shown in red. Once activated, TLR4 down-regulates BVRA and PKCζ expression (dashed lines). TLR4 upregulates expression of MMP99, which then triggers AMPKα cleavage (dashed line), leading to Raptor Ser792 dephosphorylation9. This enables mTORC1 activation, which then triggers an increase in HIF-1α expression and S6K1 phosphorylation at Thr389. TLR4 also triggers an increase in haptoglobin expression, thus limiting heme availability. Using these parallel mechanisms TLR4 ensures biliverdin/BVRA and mTORC2 signaling inhibition, and on the other hand, mTORC1 activation.
