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Design and Evaluation of a Multihoming-Based Mobility Management Scheme to Support Inter Technology Handoff in PNEMO
Handoff management is an indispensable component in supporting network mobility. The handoff situation raises while the Mobile Router (MR) or Mobile Node (MN) crosses the different wireless communication access technologies. At the time of inter technology handoff the multiple interface based MR can accomplish multihoming features such as enhanced availability, traffic load balancing with seamless flow distribution. These multihoming topographies greatly responsible reducing network delays during inter technology handoff. This article proposes a multihoming based Mobility management in Proxy NEMO (MM-PNEMO) scheme that considers benefits of using multiple interfaces. To support the proposed scheme design a numerical framework is developed that will be used to assess the performance of the proposed MM-PNEMO scheme. The performance is evaluated in the state-of-art numerical simulation approach focusing the key success metrics of signalling cost and packet delivery cost, that eventually scaling the total handoff cost. The numerical simulation result shows that the proposed MM-PENMO delightedly reduces the average handoff cost to 60% compared to existing NEMO Basic support protocol (NEMO-BSP) and PNEMO.
Journal Article
Young Captain Nemo
Twelve-year-old Gabriel Nemo--a descendant of Captain Nemo himself--and his friends embark on a series of worldwide underwater adventures in Nemo's Nemotech submarine.
Book
NEMO specifically recognizes K63-linked poly-ubiquitin chains through a new bipartite ubiquitin-binding domain
An important property of NEMO, the core element of the IKK complex involved in NF‐κB activation, resides in its ability to specifically recognize poly‐ubiquitin chains. A small domain called NOA/UBAN has been suggested to be responsible for this property. We recently demonstrated that the C‐terminal Zinc Finger (ZF) of NEMO is also able to bind ubiquitin. We show here by ZF swapping and mutagenesis that this represents its only function. While neither NOA nor ZF shows any preference for K63‐linked chains, we demonstrate that together they form a bipartite high‐affinity K63‐specific ubiquitin‐binding domain. A similar domain can be found in two other proteins, Optineurin and ABIN2, and can be freely exchanged with that of NEMO without interfering with its activity. This suggests that the main function of the C‐terminal half of NEMO is to specifically bind K63‐linked poly‐ubiquitin chains. We also demonstrate that the recently described binding of NEMO to linear poly‐ubiquitin chains is dependent on the NOA alone and does not require the presence of the ZF.
Journal Article
Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains
At least eight types of ubiquitin chain exist, and individual linkages affect distinct cellular processes. The only distinguishing feature of differently linked ubiquitin chains is their structure, as polymers of the same unit are chemically identical. Here, we have crystallized Lys 63‐linked and linear ubiquitin dimers, revealing that both adopt equivalent open conformations, forming no contacts between ubiquitin molecules and thereby differing significantly from Lys 48‐linked ubiquitin chains. We also examined the specificity of various deubiquitinases (DUBs) and ubiquitin‐binding domains (UBDs). All analysed DUBs, except CYLD, cleave linear chains less efficiently compared with other chain types, or not at all. Likewise, UBDs can show chain specificity, and are able to select distinct linkages from a ubiquitin chain mixture. We found that the UBAN (ubiquitin binding in ABIN and NEMO) motif of NEMO (NF‐κB essential modifier) binds to linear chains exclusively, whereas the NZF (Npl4 zinc finger) domain of TAB2 (TAK1 binding protein 2) is Lys 63 specific. Our results highlight remarkable specificity determinants within the ubiquitin system.
Journal Article
The E3 ligase HOIL-1 catalyses ester bond formation between ubiquitin and components of the Myddosome in mammalian cells
The linear ubiquitin assembly complex (LUBAC) comprises 3 components: HOIP, HOIL-1, and Sharpin, of which HOIP and HOIL-1 are both members of the RBR subfamily of E3 ubiquitin ligases. HOIP catalyses the formation of Met1-linked ubiquitin oligomers (also called linear ubiquitin), but the function of the E3 ligase activity of HOIL-1 is unknown. Here, we report that HOIL-1 is an atypical E3 ligase that forms oxyester bonds between the C terminus of ubiquitin and serine and threonine residues in its substrates. Exploiting the sensitivity of HOIL-1–generated oxyester bonds to cleavage by hydroxylamine, and macrophages from knock-in mice expressing the E3 ligase-inactive HOIL-1[C458S] mutant, we identify IRAK1, IRAK2, and MyD88 as physiological substrates of the HOIL-1 E3 ligase during Toll-like receptor signaling. HOIL-1 is a monoubiquitylating E3 ubiquitin ligase that initiates the de novo synthesis of polyubiquitin chains that are attached to these proteins in macrophages. HOIL-1 also catalyses its own monoubiquitylation in cells and most probably the monoubiquitylation of Sharpin, in which ubiquitin is also attached by an oxyester bond. Our study establishes that oxyester-linked ubiquitylation is used as an intracellular signaling mechanism.
Journal Article
The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues
Tumor necrosis factor alpha (TNF; TNFα) is a critical regulator of immune responses in healthy organisms and in disease. TNF is involved in the development and proper functioning of the immune system by mediating cell survival and cell death inducing signaling. TNF stimulated signaling pathways are tightly regulated by a series of phosphorylation and ubiquitination events, which enable timely association of TNF receptors-associated intracellular signaling complexes. Disruption of these signaling events can disturb the balance and the composition of signaling complexes, potentially resulting in severe inflammatory diseases.
Journal Article
Novel small molecule inhibition of IKK/NF‐κB activation reduces markers of senescence and improves healthspan in mouse models of aging
Constitutive NF‐κB activation is associated with cellular senescence and stem cell dysfunction and rare variants in NF‐κB family members are enriched in centenarians. We recently identified a novel small molecule (SR12343) that inhibits IKK/NF‐κB activation by disrupting the association between IKKβ and NEMO. Here we investigated the therapeutic effects of SR12343 on senescence and aging in three different mouse models. SR12343 reduced senescence‐associated beta‐galactosidase (SA‐β‐gal) activity in oxidative stress‐induced senescent mouse embryonic fibroblasts as well as in etoposide‐induced senescent human IMR90 cells. Chronic administration of SR12343 to the Ercc1−/∆ and Zmpste24−/− mouse models of accelerated aging reduced markers of cellular senescence and SASP and improved multiple parameters of aging. SR12343 also reduced markers of senescence and increased muscle fiber size in 2‐year‐old WT mice. Taken together, these results demonstrate that IKK/NF‐κB signaling pathway represents a promising target for reducing markers of cellular senescence, extending healthspan and treating age‐related diseases. Constitutive IKK/NF‐κB activation is associated with cellular senescence and aging. Here we demonstrate that pharmacological inhibition of IKK/NF‐κB activation by the small molecule SR12343 reduced senescence and SAPS factors in cell culture, improved healthspan in mice with accelerated aging, and reduced markers of senescence and pathology in multiple tissues of both accelerated and naturally aged mice. Therefore, IKK/NF‐κB pathway is a promising target for aging interventions to treat age‐related diseases.
Journal Article
NLK facilitates Caspase‐8 activation to drive macrophage PANoptosis in sepsis
Mounting evidence indicates that macrophage PANoptosis-an integrated inflammatory cell-death program comprising pyroptosis, apoptosis, and necroptosis-plays a pivotal role in sepsis pathogenesis. However, its upstream regulation remains poorly understood. Here, we identify Nemo-like kinase (NLK) as a novel regulator of Caspase-8-mediated PANoptotic signalling in sepsis. Integrated analyses of bulk (GSE65682) and single-cell (GSE167363) transcriptomic datasets from patients with sepsis revealed elevated NLK expression in monocytes, strongly associated with PANoptotic effectors and adverse outcomes. Functional studies using NLK conditional knockout mice driven by Csf1r-iCre and lipopolysaccharide-stimulated bone-marrow-derived macrophages showed that NLK deficiency attenuated Caspase-8 cleavage, suppressed pyroptotic (cleaved Caspase-1, GSDMD-N) and apoptotic (cleaved Caspase-3/7) activation, and redirected cell-death execution towards a necroptosis-dominant program (p-RIPK1/3, p-MLKL). This death-mode redistribution was associated with attenuated cytokine release, reduced multiorgan injury, and improved survival. Mechanistically, NLK associated with the N-terminal death effector domains (DEDs; amino acids 1-216) of Caspase-8, thereby enhancing the efficiency of Caspase-8 recruitment and proximity-induced activation within FADD-RIPK1/3-containing PANoptosome complexes. NLK deletion impaired Caspase-8 activation within these complexes and promoted RIPK1-RIPK3 necrosome assembly. Moreover, Caspase-8 overexpression in NKO macrophages partially restored GSDMD and Caspase-3 cleavage and reduced p-MLKL, confirming that NLK is required for efficient Caspase-8 activation and optimal PANoptotic signalling. Collectively, these findings identify NLK as a regulatory rheostat of Caspase-8-associated PANoptosis in sepsis and highlight the NLK-Caspase-8 axis as a potential therapeutic target for fine-tuning sepsis-associated inflammatory cell death.
Journal Article
Critical Roles of NF-κB Signaling Molecules in Bone Metabolism Revealed by Genetic Mutations in Osteopetrosis
The nuclear factor-κB (NF-κB) transcription factor family consists of five related proteins, RelA (p65), c-Rel, RelB, p50/p105 (NF-κB1), and p52/p100 (NF-κB2). These proteins are important not only for inflammation and the immune response but also for bone metabolism. Activation of NF-κB occurs via the classic and alternative pathways. Inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, activate the former, and cytokines involved in lymph node formation, such as receptor activator of NF-κB ligand (RANKL) and CD40L, activate the latter. p50 and p52 double-knockout mice revealed severe osteopetrosis due to the total lack of osteoclasts, which are specialized cells for bone resorption. This finding suggests that the activation of NF-κB is required for osteoclast differentiation. The NF-κB signaling pathway is controlled by various regulators, including NF-κB essential modulator (NEMO), which is encoded by the IKBKG gene. In recent years, mutant forms of the IKBKG gene have been reported as causative genes of osteopetrosis, lymphedema, hypohidrotic ectodermal dysplasia, and immunodeficiency (OL-EDA-ID). In addition, a mutation in the RELA gene, encoding RelA, has been reported for the first time in newborns with high neonatal bone mass. Osteopetrosis is characterized by a diffuse increase in bone mass, ranging from a lethal form observed in newborns to an asymptomatic form that appears in adulthood. This review describes the genetic mutations in NF-κB signaling molecules that have been identified in patients with osteopetrosis.
Journal Article