Invariant chain induces B cell maturation by activating a TAF(II)105-NF-kappaB-dependent transcription program.

Early stages of B cell development occur in the bone marrow, resulting in formation of immature B cells. From there these immature cells migrate to the spleen where they differentiate to mature cells. This final maturation step is crucial for the B cells to become responsive to antigens and to participate in the immune response. Recently, invariant chain (Ii), a major histocompatibility complex class II chaperone, as well as the transcription factors c-Rel and p65/RelA, were found to play a role in the final antigen-independent differentiation stage of B cells in the spleen. In this study, we investigated a possible link between Ii-dependent B cell maturation and the NF-kappaB pathway. Our studies indicate that Ii-induced B cell maturation involves activation of transcription mediated by the NF-kappaB p65/RelA homodimer and requires the B cell-enriched coactivator TBP-associated factor (II)105.

Interaction of TAFII105 with selected p65/RelA dimers is associated with activation of subset of NF-kappa B genes.

TAF(II)105, a substoichiometric coactivator subunit of TFIID, is important for activation of anti-apoptotic genes by NF-kappaB in response to the cytokine tumor necrosis factor (TNF)-alpha. In the present study we have analyzed the mechanism of TAF(II)105 function with respect to its regulation of p65/RelA, a component of NF-kappaB. We found two independent p65/RelA-binding domains within the N terminus of TAF(II)105. One of these domains appears to be crucial for TAF(II)105-mediated anti-apoptotic gene activation in response to TNF-alpha. Analysis of the interaction between TAF(II)105 and different NF-kappaB complexes has revealed substantial differences in the affinity of TAF(II)105 toward different p65/RelA-containing dimers. We have identified the TNF-alpha induced anti-apoptotic A20 gene as a target gene of TAF(II)105. A20 has a differential protective effect on cell death induced by TNF-alpha in the presence of either the dominant negative mutant of TAF(II)105 (TAF(II)105DeltaC) or the superdominant IkappaBalpha. The results suggest that the inhibitory effect of TAF(II)105DeltaC on NF-kappaB-dependent genes is restricted to a subset of anti-apoptotic genes while the effect of IkappaBalpha is more general. Thus, an interaction between NF-kappaB and a specific coactivator is important for specifying target gene activation.

Specific interaction of TAFII105 with OCA-B is involved in activation of octamer-dependent transcription.

TAF(II)105 is a TFIID-associated factor highly expressed in B lymphocytes. This subunit is found in a small portion of TFIID complexes and is homologous to human TAF(II)130 and Drosophila TAF(II)110. In the present study we show that TAF(II)105 is involved in transcription activation directed by the B cell-specific octamer element found in many B cell-specific genes. B cells overexpressing TAF(II)105 display higher octamer-dependent transcription, whereas expression of a C-terminal truncated form of TAF(II)105 inhibits octamer transcription in a dominant negative manner. In addition, antibodies directed against TAF(II)105 specifically inhibit octamer-dependent transcription. Reporter gene analysis revealed that TAF(II)105 elevates octamer transcription in the presence of OCA-B, a cofactor subunit of Oct1 and Oct2 proteins. In vitro binding assays and functional studies established that the effect of TAF(II)105 on octamer activity involves interaction of TAF(II)105 with octamer-binding complexes via the C-terminal activation domain of OCA-B. These findings link TAF(II)105 coactivator function to B cell-specific transcription.