35
PLoS One. 2012;7(7):e41005.
The inositol phosphatase SHIP-1 inhibits NOD2-
induced NF-κB activation by disturbing the interac-
tion of XIAP with RIP2.
Condé C, Rambout X, Lebrun M, Lecat A, Di Valentin E, Dequiedt F, Piette J, Gloire G, Legrand S.
Abstract
SHIP-1 is an inositol phosphatase predominantly expressed in hematopoietic cells. Over the
ten past years, SHIP-1 has been described as an important regulator of immune functions.
Here, we characterize a new inhibitory function for SHIP-1 in NOD2 signaling. NOD2 is a
crucial cytoplasmic bacterial sensor that activates proinfammatory and antimicrobial res-
ponses upon bacterial invasion. We observed that SHIP-1 decreases NOD2-induced NF-κB
activation in macrophages. This negative regulation relies on its interaction with XIAP. Indeed,
we observed that XIAP is an essential mediator of the NOD2 signaling pathway that enables
proper NF-κB activation in macrophages. Upon NOD2 activation, SHIP-1 C-terminal proline
rich domain (PRD) interacts with XIAP, thereby disturbing the interaction between XIAP and
RIP2 in order to decrease NF-κB signaling.
Nature. 2012 Mar 25;484(7394):386-9.
DBIRD complex integrates alternative mRNA
splicing with RNA polymerase II transcript
elongation.
Close P, East P, Dirac-Svejstrup AB, Hartmann H, Heron M, Maslen S, Chariot A, Söding J,
Skehel M, Svejstrup JQ.
.
Abstract
Alternative messenger RNA splicing is the main reason that vast mammalian proteomic
complexitycanbeachievedwitha limitednumberofgenes. Splicing isphysicallyandfunctionally
coupledtotranscription,andisgreatlyafectedbytherateoftranscriptelongation. Asthenascent
pre-mRNA emerges from transcribing RNA polymerase II (RNAPII), it is assembled into
a messenger ribonucleoprotein (mRNP) particle; this is the functional form of the nascent
pre-mRNA and determines the fate of the mature transcript. However, factors that connect
the transcribing polymerase with the mRNP particle and help to integrate transcript elon-
gation with mRNA splicing remain unclear. Here we characterize the human interactome of
chromatin-associated mRNP particles. This led us to identify deleted in breast cancer 1 (DBC1)
and ZNF326 (which we call ZNF-protein interacting with nuclear mRNPs and DBC1 (ZIRD)) as
subunits of a novel protein complex--named DBIRD--that binds directly to RNAPII. DBIRD
regulates alternative splicing of a large set of exons embedded in (A + T)-rich DNA, and
is present at the afected exons. RNA-interference-mediated DBIRD depletion results in
region-specifc decreases in transcript elongation, particularly across areas encompassing
afected exons. Together, these data indicate that the DBIRD complex acts at the interface
between mRNP particles and RNAPII, integrating transcript elongation with the regulation of
alternative splicing.