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Beichu Guo

Publications and source records attributed to Beichu Guo.

6 recordsLinked to original sources
PubMed2005

Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response.

Type I interferon (IFN) production is a critical component of the innate defence against viral infections. Viral products induce strong type I IFN responses through the activation of Toll-like receptors (TLRs) and intracellular cytoplasmic receptors such as protein kinase R (PKR). Here we demonstrate that cells lacking TRAF3, a member of the TNF receptor-associated factor family, are defective in type I IFN responses activated by several different TLRs. Furthermore, we show that TRAF3 associates with the TLR adaptors TRIF and IRAK1, as well as downstream IRF3/7 kinases TBK1 and IKK-epsilon, suggesting that TRAF3 serves as a critical link between TLR adaptors and downstream regulatory kinases important for IRF activation. In addition to TLR stimulation, we also show that TRAF3-deficient fibroblasts are defective in their type I IFN response to direct infection with vesicular stomatitis virus, indicating that TRAF3 is also an important component of TLR-independent viral recognition pathways. Our data demonstrate that TRAF3 is a major regulator of type I IFN production and the innate antiviral response.

Adaptor Proteins, Vesicular Transport↗
PubMed2005

Phosphorylation of the CARMA1 linker controls NF-kappaB activation.

PKC isoforms and CARMA1 play crucial roles in immunoreceptor-dependent NF-kappaB activation. We tested whether PKC-dependent phosphorylation of CARMA1 directly regulates this signaling cascade. B cell antigen receptor (BCR) engagement led to the progressive recruitment of CARMA1 into lipid rafts and to the association of CARMA1 with, and phosphorylation by, PKCbeta. Furthermore, PKCbeta interacted with the serine-rich CARMA1 linker, and both PKCbeta and PKCtheta phosphorylated identical serine residues (S564, S649, and S657) within this linker. Mutation of two of these sites ablated the functional activity of CARMA1. In contrast, deletion of the linker resulted in constitutive, receptor- and PKC-independent NF-kappaB activation. Together, our data support a model whereby CARMA1 phosphorylation controls NF-kappaB activation by triggering a shift from an inactive to an active CARMA1 conformer. This PKC-dependent switch regulates accessibility of the CARD and CC domains and controls assembly and full activation of the membrane-associated IkappaB kinase (IKK) signalosome.

Animals↗
PubMed2004

Protein kinase C family functions in B-cell activation.

Members of the protein kinase C (PKC) family play important but distinct roles in B-cell activation, as demonstrated by emerging genetic and biochemical studies. PKCbeta is indispensable for B-cell antigen receptor (BCR)-induced NF-kappaB activation and B-cell survival. Recent evidence indicates that PKCbeta might regulate inhibitor of kappaB kinase (IKK) and NF-kappaB activation through interaction with the CARMA1/Bcl10/MALT signaling complex in BCR microdomains. By contrast, the novel PKC isoform PKCdelta is specifically required to maintain the tolerance of self-reactive B cells.

Animals↗
PubMed2004

Signaling in transitional type 2 B cells is critical for peripheral B-cell development.

Splenic peripheral B-cell development and the events regulating this functionally significant but relatively poorly defined developmental process have become a major focus in recent studies in B-cell immunology. Following the exit from the bone marrow, peripheral B cells develop through transitional type 1 (T1) and transitional type 2 (T2) B-cell stages. Emerging data suggest that the T2 subset is the immediate precursor of the mature B-cell populations present in the spleen. In this review, we first elaborate on the evidence describing the unique properties of CD21hiCD24hiCD23hiIgMhiIgDhi T2 B cells. T2 cells uniquely activate a proliferative, pro-survival, and differentiation program in response to B-cell antigen receptor (BCR) engagement. The potential mechanisms leading to the differential BCR responsiveness of T1 versus T2 B cells are discussed. We also review evidence that distinguishes key BCR-dependent signaling pathways operative in T2 and mature B cells. These signaling cascades include a protein kinase Cbeta (PKCbeta)-dependent cell-survival pathway and a second PKCbeta-independent pathway essential for BCR-driven differentiation. Finally, we discuss recent intriguing results suggesting that the type of signal(s) encountered by T2 cells leads to their differential maturation toward the follicular mature versus marginal zone mature B-cell populations. These combined observations suggest important implications with regard to B-cell selection and tolerance, potential novel therapeutic targets for B-cell lymphomas, and how the intricate balance of commensal organisms and other microenvironmental signals interact to promote the generation of 'innate-like' versus adaptive effector B-cell populations.

Animals↗
PubMed2002

PKC-beta controls I kappa B kinase lipid raft recruitment and activation in response to BCR signaling.

NF-kappa B signaling is required for the maintenance of normal B lymphocytes, whereas dysregulated NF-kappa B activation contributes to B cell lymphomas. The events that regulate NF-kappa B signaling in B lymphocytes are poorly defined. Here, we demonstrate that PKC-beta is specifically required for B cell receptor (BCR)-mediated NF-kappa B activation. B cells from protein kinase C-beta (PKC-beta)-deficient mice failed to recruit the I kappa B kinase (IKK) complex into lipid rafts, activate IKK, degrade I kappa B or up-regulate NF-kappa B-dependent survival signals. Inhibition of PKC-beta promoted cell death in B lymphomas characterized by exaggerated NF-kappa B activity. Together, these data define an essential role for PKC-beta in BCR survival signaling and highlight PKC-beta as a key therapeutic target for B-lineage malignancies.

Animals↗