SHARPIN is a ubiquitin-binding and ubiquitin-like domain-containing protein which, when mutated in mice, results in immune system disorders and multiorgan inflammation1,2. Here we report that SHARPIN functions as a novel component of the Linear Ubiquitin Chain Assembly Complex (LUBAC) and that the absence of SHARPIN causes disregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis in SHARPIN deficient mice. Upon binding to the LUBAC subunit HOIP, SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Co-expression of SHARPIN and HOIP promotes linear ubiquitylation of NEMO, an adaptor of the IκB kinases (IKKs) and subsequent activation of NF-κB signalling, while SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-κB in B cells, macrophages, and mouse embryonic fibroblasts (MEFs). This effect is further enhanced upon concurrent downregulation of HOIL-1L, another HOIP-binding component of LUBAC. In addition, SHARPIN deficiency leads to rapid cell death upon TNFα stimulation via FADD- and Caspase-8-dependent pathways. SHARPIN thus activates NF-κB and inhibits apoptosis via distinct pathways in vivo.

E-cadherin controls a wide array of cellular behaviors including cell-cell adhesion, differentiation and tissue development. Here we show that presenilin-1 (PS1), a protein involved in Alzheimer's disease, controls a gamma-secretase-like cleavage of E-cadherin. This cleavage is stimulated by apoptosis or calcium influx and occurs between human E-cadherin residues Leu731 and Arg732 at the membrane-cytoplasm interface. The PS1/gamma-secretase system cleaves both the full-length E-cadherin and a transmembrane C-terminal fragment, derived from a metalloproteinase cleavage after the E-cadherin ectodomain residue Pro700. The PS1/gamma-secretase cleavage dissociates E-cadherins, beta-catenin and alpha-catenin from the cytoskeleton, thus promoting disassembly of the E-cadherin-catenin adhesion complex. Furthermore, this cleavage releases the cytoplasmic E-cadherin to the cytosol and increases the levels of soluble beta- and alpha-catenins. Thus, the PS1/gamma-secretase system stimulates disassembly of the E-cadherin- catenin complex and increases the cytosolic pool of beta-catenin, a key regulator of the Wnt signaling pathway.

Matrix metalloproteinases (MMPs) are extracellular proteases that have well recognized roles in cell signaling and remodeling in many tissues. In the brain, their activation and function are customarily associated with injury or pathology. Here, we demonstrate a novel role for MMP-9 in hippocampal synaptic physiology, plasticity, and memory. MMP-9 protein levels and proteolytic activity are rapidly increased by stimuli that induce late-phase long-term potentiation (L-LTP) in area CA1. Such regulation requires NMDA receptors and protein synthesis. Blockade of MMP-9 pharmacologically prevents induction of L-LTP selectively; MMP-9 plays no role in, nor is regulated during, other forms of short-term synaptic potentiation or long-lasting synaptic depression. Similarly, in slices from MMP-9 null-mutant mice, hippocampal LTP, but not long-term depression, is impaired in magnitude and duration; adding recombinant active MMP-9 to null-mutant slices restores the magnitude and duration of LTP to wild-type levels. Activated MMP-9 localizes in part to synapses and modulates hippocampal synaptic physiology through integrin receptors, because integrin function-blocking reagents prevent an MMP-9-mediated potentiation of synaptic signal strength. The fundamental importance of MMP-9 function in modulating hippocampal synaptic physiology and plasticity is underscored by behavioral impairments in hippocampal-dependent memory displayed by MMP-9 null-mutant mice. Together, these data reveal new functions for MMPs in synaptic and behavioral plasticity.

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Bozdagi O, Nagy V, Kwei KT, Huntley GW. In vivo roles for matrix metalloproteinase-9 in mature hippocampal synaptic physiology and plasticity. J Neurophysiol 98: 334 -344, 2007. First published May 9, 2007; doi:10.1152/jn.00202.2007. Extracellular proteolysis is an important regulatory nexus for coordinating synaptic functional and structural plasticity, but the identity of such proteases is incompletely understood. Matrix metalloproteinases (MMPs) have wellknown, mostly deleterious roles in remodeling after injury or stroke, but their role in nonpathological synaptic plasticity and function in intact adult brains has not been extensively investigated. Here we address the role of MMP-9 in hippocampal synaptic plasticity using both gain-and loss-of-function approaches in urethane-anesthetized adult rats. Acute blockade of MMP-9 proteolytic activity with inhibitors or neutralizing antibodies impairs maintenance, but not induction, of long-term potentiation (LTP) at synapses formed between Schaffer-collaterals and area CA1 dendrites. LTP is associated with significant increases in levels of MMP-9 and proteolytic activity within the potentiated neuropil. By introducing a novel application of gelatin-substrate zymography in vivo, we find that LTP is associated with significantly elevated numbers of gelatinolytic puncta in the potentiated neuropil that codistribute with immunolabeling for MMP-9 and for markers of synapses and dendrites. Such increases in proteolytic activity require NMDA receptor activation. Exposing intact area CA1 neurons to recombinant-active MMP-9 induces a slow synaptic potentiation that mutually occludes, and is occluded by, tetanically evoked potentiation. Taken together, our data reveal novel roles for MMP-mediated proteolysis in regulating nonpathological synaptic function and plasticity in mature hippocampus.

Our results infer that cessation of ovarian estrogen production in postmenopausal women might facilitate Abeta deposition by increasing the local concentrations of Abeta40 and Abeta42 peptides in brain. In addition, our finding that E2 treatment is associated with diminution of brain Abeta levels suggests that modulation of Abeta metabolism may be one of the ways by which estrogen replacement therapy prevents or delays the onset of AD or both in postmenopausal women.

Receptor activator of nuclear factor κB (RANK) and its ligand (RANKL) have originally been described for their key roles in bone metabolism and the immune system. Subsequently, it has been shown that the RANKL-RANK system is critical in the formation of mammary epithelia in lactating females and the thermoregulation of the central nervous system. RANKL and RANK are under the tight control of the female sex hormones estradiol and progesterone. A reduction of the circulating female sex hormones leading to an increase in RANKL-RANK signaling is the leading cause of osteoporosis in postmenopausal women. Denosumab, a human monoclonal anti-RANKL antibody, has been approved for the treatment of postmenopausal osteoporosis, where it is showing great promise. In addition, RANKL-RANK signaling also plays a critical role in other bone pathologies, bone metastasis or hormone-driven breast cancer. This review will highlight some of the functions of RANKL-RANK in bone turnover, the immune system and brain with a focus on the regulatory role of the female sex hormones.

Highlights d In somatosensory ganglia, Prdm12 is specific to the nociceptive lineage d Prdm12 is necessary for the survival of developing nociceptors d Prdm12 initiates and maintains the expression of TrkA in developing nociceptors d Prdm12 acts in conjunction with bHLH proteins Ngn1/2 to promote a nociceptor fate