ABIN2 Function Is Required To Suppress DSS-Induced Colitis by a Tpl2-Independent Mechanism

Abstract

The A20-binding inhibitor of NF-κB 2 (ABIN2) interacts with Met1-linked ubiquitin chains and is an integral component of the tumor progression locus 2 (Tpl2) kinase complex. We generated a knock-in mouse expressing the ubiquitin-binding–defective mutant ABIN2[D310N]. The expression of Tpl2 and its activation by TLR agonists in macrophages or by IL-1β in fibroblasts from these mice was unimpaired, indicating that the interaction of ABIN2 with ubiquitin oligomers is not required for the stability or activation of Tpl2. The ABIN2[D310N] mice displayed intestinal inflammation and hypersensitivity to dextran sodium sulfate–induced colitis, an effect that was mediated by radiation-resistant cells rather than by hematopioetic cells. The IL-1β–dependent induction of cyclooxygenase 2 (COX2) and the secretion of PGE2 was reduced in mouse embryonic fibroblasts and intestinal myofibroblasts (IMFs) from ABIN2[D310N] mice. These observations are similar to those reported for the Tpl2 knockout (KO) mice (Roulis et al. 2014. Proc. Natl. Acad. Sci. USA 111: E4658–E4667), but the IL-1β–dependent production of COX2 and PGE2 in mouse embryonic fibroblasts or IMFs was unaffected by pharmacological inhibition of Tpl2 in wild-type mice. The expression of ABIN2 is decreased drastically in Tpl2 KO mice. These and other lines of evidence suggest that the hypersensitivity of Tpl2 KO mice to dextran sodium sulfate–induced colitis is not caused by the loss of Tpl2 catalytic activity but by the loss of ABIN2, which impairs COX2 and PGE2 production in IMFs by a Tpl2 kinase–independent pathway.

ULK1/2 Restricts the Formation of Inducible SINT-Speckles, Membraneless Organelles Controlling the Threshold of TBK1 Activation

“…This implies that physiological variations in the amounts of SINT-speckle proteins can already affect speckle formation. Regulation of ABIN2 protein levels occurs in the presence of increased glucose levels or by the kinases TPL2 or IKKα/β (Chen et al., 2013, Leotoing et al., 2011, Nanda et al., 2018), and it will thus be interesting to investigate whether these situations will affect the formation of SINT-speckles. The formation of inducible SINT-speckles is regulated by several mechanisms, as schematically shown in Figure 9B.…”

Distinct signals and immune cells drive liver pathology and glomerulonephritis in ABIN1[D485N] mice

“…WT mice expressing CD45.1 (∼120 d old) were lethally irradiated (Nanda et al, 2018) and reconstituted with bone marrow cells (2.5 × 10 6 in PBS) via tail vein injection. Following reconstitution, mice received prophylactic antibiotics in their drinking water.…”

Kinase inhibition in autoimmunity and inflammation

“…This selective action of TPL2 on specific MAPKs is intriguing and should expand the utility of this target for several indications (see below). Recent studies with catalytically inactive ABIN2 (D310N) in gut inflammation showed that ABIN2 regulates IL-1β-dependent induction of cyclooxygenase 2 (COX2) and PGE2 secretion 189 , functions previously thought to be regulated by TPL2 (ref. 190 ).…”