A critical step in the activation of NF-B is the phosphorylation of IBs by the IB kinase (IKK) complex. IKK␣ and IKK␤ are the two catalytic subunits of the IKK complex and two additional molecules, IKK␥/NEMO and IKAP, have been described as further integral members. We have analyzed the function of both proteins for IKK complex composition and NF-B signaling. IKAP and IKK␥ belong to distinct cellular complexes. Quantitative association of IKK␥ was observed with IKK␣ and IKK␤. In contrast IKAP was complexed with several distinct polypeptides. Overexpression of either IKK␥ or IKAP blocked tumor necrosis factor ␣ induction of an NF-Bdependent reporter construct, but IKAP in addition affected several NF-B-independent promoters. Whereas specific down-regulation of IKK␥ protein levels by antisense oligonucleotides significantly reduced cytokinemediated activation of the IKK complex and subsequent NF-B activation, a similar reduction of IKAP protein levels had no effect on NF-B signaling. Using solely IKK␣, IKK␤, and IKK␥, we could reconstitute a complex whose apparent molecular weight is comparable to that of the endogenous IKK complex. We conclude that while IKK␥ is a stoichiometric component of the IKK complex, obligatory for NF-B signaling, IKAP is not associated with IKKs and plays no specific role in cytokine-induced NF-B activation.NF-B transcription factors play a pivotal role in many cellular processes such as inflammation, immune response, cell proliferation, and apoptosis (1-5). The prototype of the NF-B family is a heterodimer of the p50 and p65 (RelA) subunits. IB proteins (IB␣, IB␤, IB⑀, p105, and p100) retain NF-B in an inactive form in the cytoplasm. A conserved ankyrin repeat domain in these inhibitors masks nuclear translocation signals contained in the Rel homology domain of NF-B.In response to multiple stimuli, including TNF␣, 1 IL-1␤, phorbol ester, and lipopolysaccharides, NF-B is liberated from IB molecules and translocates to the nucleus (6). This critical step of NF-B activation is initiated by phosphorylation of IB proteins at conserved amino-terminal serine residues, e.g. at serines 32 and 36 of IB␣ or serines 19 and 23 of IB␤. Phosphorylated IBs are bound by a ␤TrCP containing ubiquitin ligase (E3) complex, polyubiquitinated and subsequently degraded by the 26 S proteasome (7).Most NF-B-inducing stimuli trigger activation of an IB kinase (IKK) complex with a high apparent molecular mass of 700 -900 kDa (8, 9), which has specificity for the amino-terminal phosphoacceptor sites in IB␣ or -␤. The kinase complex contains two catalytic subunits termed IKK␣ (IKK1) and IKK␤ (IKK2) (8, 10 -13). IKK␣ and IKK␤ are related molecules of 85 and 87 kDa, respectively, with an overall identity of about 44%. Both contain an NH 2 -terminal kinase domain, a leucine zipper and a COOH-terminal helix-loop-helix motif. IKK␣ and IKK␤ form homo-or heterodimers via their leucine zipper (for review, see Ref. 14). Both kinases are stimulated by proinflammatory cytokines and their activation kinetics match that of IB␣ p...

Schwann cells in the peripheral nervous systems extend their membranes to wrap axons concentrically and form the insulating sheath, called myelin. The spaces between layers of myelin are sealed by myelin junctions. This tight insulation enables rapid conduction of electric impulses (action potentials) through axons. Demyelination (stripping off the insulating sheath) has been widely regarded as one of the most important mechanisms altering the action potential propagation in many neurological diseases. However, the effective nerve conduction is also thought to require a proper myelin seal through myelin junctions such as tight junctions and adherens junctions. In the present study, we have demonstrated the disruption of myelin junctions in a mouse model (Pmp22+/-) of hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of Pmp22 gene. We observed a robust increase of F-actin in Pmp22+/- nerve regions where myelin junctions were disrupted, leading to increased myelin permeability. These abnormalities were present long before segmental demyelination at the late phase of Pmp22+/- mice. Moreover, the increase of F-actin levels correlated with an enhanced activity of p21-activated kinase (PAK1), a molecule known to regulate actin polymerization. Pharmacological inhibition of PAK normalized levels of F-actin, and completely prevented the progression of the myelin junction disruption and nerve conduction failure in Pmp22+/- mice. Our findings explain how abnormal myelin permeability is caused in HNPP, leading to impaired action potential propagation in the absence of demyelination. We call it “functional demyelination”, a novel mechanism upstream to the actual stripping of myelin that is relevant to many demyelinating diseases. This observation also provides a potential therapeutic approach for HNPP.

The involvement of genetic risk and the underlying developmental and neural circuit mechanisms in autism-related social deficit are largely unclear. Here, we report that deletion of AUTS2 , a high-susceptibility gene of ASDs, caused postnatal dentate gyrus (DG) hypoplasia, which was closely relevant to social recognition deficit. Furthermore, a previously unknown mechanism for neural cell migration in postnatal DG development was identified, in which Auts2-related signaling played a vital role as the transcription repressor. Moreover, the supramammillary nucleus (SuM)–DG-CA3 neural circuit was found to be involved in social recognition and affected in Auts2 -deleted mice due to DG hypoplasia. Correction of DG-CA3 synaptic transmission by using a pharmacological approach or chemo/optogenetic activation of the SuM-DG circuit restored the social recognition deficit in Auts2 -deleted mice. Our findings demonstrated the vital role of Auts2 in postnatal DG development, and this role was critical for SuM-DG-CA3 neural circuit-mediated social recognition behavior.