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Sci. Signal., 27 November 2012
Vol. 5, Issue 252, p. ec305
[DOI: 10.1126/scisignal.2003808]

EDITORS' CHOICE

Immunology Bcl10 Does Double Duty

Annalisa M. VanHook

Science Signaling, AAAS, Washington, DC 20005, USA

Bcl10 (B cell lymphoma/leukemia-10) promotes immune responses downstream of antigen receptors and phagocytic receptors by stimulating nuclear factor {kappa}B (NF-{kappa}B) signaling and by stimulating phagocytosis of antigenic particles. After activation of antigen receptors, a complex consisting of Carma1, Bcl10, and Malt1 (the CBM complex) recruits and activates the inhibitor of {kappa}B kinase complex, thus leading to release and nuclear translocation of the NF-{kappa}B dimers that mediate a transcriptional response to antigen. The mechanism by which Bcl10 promotes internalization of antigenic particles downstream of phagocytic receptors has been unclear. Marion et al. report that Bcl10 interacted with the clathrin adaptor proteins AP1 and EpsinR and promoted the delivery of a vesicular phosphatase that plays a critical role in phagocytosis. Phagocytosis begins with the formation of cup-shaped invaginations on the plasma membrane, followed by the formation of pseudopods that extend around the particle to enlarge and close the phagosome, thus internalizing the particle. In human and mouse monocytes in which Bcl10 was reduced or absent, phagocytosis of immunoglobulin G (IgG)–coated red blood cells, which is mediated by the Fc receptor (FcR), was initiated, as indicated by the formation of phagocytic cups, but most of these phagocytic cups stalled—failed to elongate and internalize—and eventually disappeared. Although CBM complexes and other NF-{kappa}B signaling components accumulated at sites of phagocytosis, Bcl10-mediated activation of NF-{kappa}B signaling was not required for Bcl10-mediated closure of phagocytic cups. In Bcl10-deficient cells, F-actin and phosphatidylinoitol-4,5-bisphosphate [PI(4,5)P2], which is required for phagocytic pseudopod formation, accumulated in stalled phagocytic cups, and treatment with low concentrations of the actin depolymerizing drug Latrunculin-A rescued stalled phagocytosis. Fluorescence and electron microscopy revealed that intracellular vesicles were targeted to a zone of depolymerized actin at the base of phagocytic cups in control cells but did not accumulate near the F-actin–enriched phagocytic cups of Bcl10-deficient cells. EpsinR and AP1 localize to endosomes and the trans-Golgi network, where they participate in protein trafficking and vesicular budding. Both EpsinR and AP1 coimmunoprecipitated with Bcl10 and accumulated at nascent phagosomes in control, but not Bcl10-deficient, cells. The phosphatidylinositol polyphosphate 5-phosphatase OCRL1 is required for phagocytosis, and its absence leads to accumulation of PI(4,5)P2 and F-actin in the cleavage furrow of dividing cells. ORCL1 colocalized with AP1 at vesicles recruited to phagocytic cups in control cells, but not in Bcl10-deficient cells, and depletion of ORCL1 reduced FcR-mediated phagocytosis and could be rescued by treatment with Latrunculin-A. The authors thus propose that OCRL1 is recruited to Bcl10-containing phagosomes through its interaction with AP1, where it promotes the actin dynamics that drive phagosome extension and closure.

S. Marion, J. Mazzolini, F. Herit, P. Bourdoncle, N. Kambou-Pene, S. Hailfinger, M. Sachse, J. Ruland, A. Benmerah, A. Echard, M. Thome, F. Niedergang, The NF-{kappa}B signaling protein Bcl10 regulates actin dynamics by controlling AP1 and OCRL-bearing vesicles. Dev. Cell 23, 954–967 (2012). [PubMed]

Citation: A. M. VanHook, Bcl10 Does Double Duty. Sci. Signal. 5, ec305 (2012).


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