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1.
EMBO J ; 42(20): e113510, 2023 10 16.
Article in English | MEDLINE | ID: mdl-37530438

ABSTRACT

Unscheduled increases in ploidy underlie defects in tissue function, premature aging, and malignancy. A concomitant event to polyploidization is the amplification of centrosomes, the main microtubule organization centers in animal cells. Supernumerary centrosomes are frequent in tumors, correlating with higher aggressiveness and poor prognosis. However, extra centrosomes initially also exert an onco-protective effect by activating p53-induced cell cycle arrest. If additional signaling events initiated by centrosomes help prevent pathology is unknown. Here, we report that extra centrosomes, arising during unscheduled polyploidization or aberrant centriole biogenesis, induce activation of NF-κB signaling and sterile inflammation. This signaling requires the NEMO-PIDDosome, a multi-protein complex composed of PIDD1, RIPK1, and NEMO/IKKγ. Remarkably, the presence of supernumerary centrosomes suffices to induce a paracrine chemokine and cytokine profile, able to polarize macrophages into a pro-inflammatory phenotype. Furthermore, extra centrosomes increase the immunogenicity of cancer cells and render them more susceptible to NK-cell attack. Hence, the PIDDosome acts as a dual effector, able to engage not only the p53 network for cell cycle control but also NF-κB signaling to instruct innate immunity.


Subject(s)
NF-kappa B , Neoplasms , Animals , Centrosome/metabolism , Inflammation/pathology , Monitoring, Immunologic , Neoplasms/metabolism , NF-kappa B/genetics , NF-kappa B/metabolism , Tumor Suppressor Protein p53/metabolism , Humans
2.
Biochem Soc Trans ; 50(2): 813-824, 2022 04 29.
Article in English | MEDLINE | ID: mdl-35343572

ABSTRACT

The death fold domain-containing protein PIDD1 has recently attracted renewed attention as a regulator of the orphan cell death-related protease, Caspase-2. Caspase-2 can activate p53 to promote cell cycle arrest in response to centrosome aberrations, and its activation requires formation of the PIDDosome multi-protein complex containing multimers of PIDD1 and the adapter RAIDD/CRADD at its core. However, PIDD1 appears to be able to engage with multiple client proteins to promote an even broader range of biological responses, such as NF-κB activation, translesion DNA synthesis or cell death. PIDD1 shows features of inteins, a class of self-cleaving proteins, to create different polypeptides from a common precursor protein that allow it to serve these diverse functions. This review summarizes structural information and molecular features as well as recent experimental advances that highlight the potential pathophysiological roles of this unique death fold protein to highlight its drug-target potential.


Subject(s)
CRADD Signaling Adaptor Protein , Caspase 2 , Apoptosis/physiology , CRADD Signaling Adaptor Protein/genetics , CRADD Signaling Adaptor Protein/metabolism , Caspase 2/genetics , Caspase 2/metabolism , Caspases/metabolism , Cell Cycle Checkpoints , Cell Death , Death Domain Receptor Signaling Adaptor Proteins/genetics , Death Domain Receptor Signaling Adaptor Proteins/metabolism , Humans , Inflammation
3.
Life Sci Alliance ; 4(4)2021 04.
Article in English | MEDLINE | ID: mdl-33536237

ABSTRACT

γ-secretase inhibitors (GSI) were developed to reduce the generation of Aß peptide to find new Alzheimer's disease treatments. Clinical trials on Alzheimer's disease patients, however, showed several side effects that worsened the cognitive symptoms of the treated patients. The observed side effects were partially attributed to Notch signaling. However, the effect on other γ-secretase substrates, such as the p75 neurotrophin receptor (p75NTR) has not been studied in detail. p75NTR is highly expressed in the basal forebrain cholinergic neurons (BFCNs) during all life. Here, we show that GSI treatment induces the oligomerization of p75CTF leading to the cell death of BFCNs, and that this event is dependent on TrkA activity. The oligomerization of p75CTF requires an intact cholesterol recognition sequence (CRAC) and the constitutive binding of TRAF6, which activates the JNK and p38 pathways. Remarkably, TrkA rescues from cell death by a mechanism involving the endocytosis of p75CTF. These results suggest that the inhibition of γ-secretase activity in aged patients, where the expression of TrkA in the BFCNs is already reduced, could accelerate cholinergic dysfunction and promote neurodegeneration.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Cholinergic Neurons/drug effects , Cholinergic Neurons/metabolism , Endocytosis , Receptor, Nerve Growth Factor/metabolism , Receptor, trkA/metabolism , Alzheimer Disease/etiology , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amino Acid Motifs , Amyloid Precursor Protein Secretases/metabolism , Cell Death/drug effects , Cycloheximide/pharmacology , Humans , Ligands , MAP Kinase Signaling System , Protein Binding , Protein Interaction Domains and Motifs , Protein Multimerization/drug effects , Proteolysis , Receptor, Nerve Growth Factor/chemistry
4.
Transl Psychiatry ; 11(1): 1, 2021 01 05.
Article in English | MEDLINE | ID: mdl-33414379

ABSTRACT

PIDD1 encodes p53-Induced Death Domain protein 1, which acts as a sensor surveilling centrosome numbers and p53 activity in mammalian cells. Early results also suggest a role in DNA damage response where PIDD1 may act as a cell-fate switch, through interaction with RIP1 and NEMO/IKKg, activating NF-κB signaling for survival, or as an apoptosis-inducing protein by activating caspase-2. Biallelic truncating mutations in CRADD-the protein bridging PIDD1 and caspase-2-have been reported in intellectual disability (ID), and in a form of lissencephaly. Here, we identified five families with ID from Iran, Pakistan, and India, with four different biallelic mutations in PIDD1, all disrupting the Death Domain (DD), through which PIDD1 interacts with CRADD or RIP1. Nonsense mutations Gln863* and Arg637* directly disrupt the DD, as does a missense mutation, Arg815Trp. A homozygous splice mutation in the fifth family is predicted to disrupt splicing upstream of the DD, as confirmed using an exon trap. In HEK293 cells, we show that both Gln863* and Arg815Trp mutants fail to co-localize with CRADD, leading to its aggregation and mis-localization, and fail to co-precipitate CRADD. Using genome-edited cell lines, we show that these three PIDD1 mutations all cause loss of PIDDosome function. Pidd1 null mice show decreased anxiety, but no motor abnormalities. Together this indicates that PIDD1 mutations in humans may cause ID (and possibly lissencephaly) either through gain of function or secondarily, due to altered scaffolding properties, while complete loss of PIDD1, as modeled in mice, may be well tolerated or is compensated for.


Subject(s)
CRADD Signaling Adaptor Protein , Intellectual Disability , Animals , CRADD Signaling Adaptor Protein/genetics , CRADD Signaling Adaptor Protein/metabolism , Caspase 2/genetics , Caspase 2/metabolism , Death Domain , Death Domain Receptor Signaling Adaptor Proteins/genetics , HEK293 Cells , Humans , India , Intellectual Disability/genetics , Mice , Mutation
5.
Article in English | MEDLINE | ID: mdl-31727679

ABSTRACT

Caspases play central roles in mediating both cell death and inflammation. It has more recently become evident that caspases also drive other biological processes. Most prominently, caspases have been shown to be involved in differentiation. Several stem and progenitor cell types rely on caspases to initiate and execute their differentiation processes. These range from neural and glial cells, to skeletal myoblasts and osteoblasts, and several cell types of the hematopoietic system. Beyond differentiation, caspases have also been shown to play roles in other "noncanonical" processes, including cell proliferation, arrest, and senescence, thereby contributing to the mechanisms that regulate tissue homeostasis at multiple levels. Remarkably, caspases directly influence the course of the cell cycle in both a positive and negative manner. Caspases both cleave elements of the cell-cycle machinery and are themselves substrates of cell-cycle kinases. Here we aim to summarize the breadth of interactions between caspases and cell-cycle regulators. We also highlight recent developments in this area.


Subject(s)
Caspases/metabolism , Cell Cycle , Cell Death , Inflammation/metabolism , Animals , Apoptosis , Cell Differentiation , Cell Division , Humans , Inflammasomes , Muscle, Skeletal/metabolism , Osteoblasts/metabolism
6.
J Biol Chem ; 291(23): 12346-57, 2016 Jun 03.
Article in English | MEDLINE | ID: mdl-27056327

ABSTRACT

Dimerization of single span transmembrane receptors underlies their mechanism of activation. p75 neurotrophin receptor plays an important role in the nervous system, but the understanding of p75 activation mechanism is still incomplete. The transmembrane (TM) domain of p75 stabilizes the receptor dimers through a disulfide bond, essential for the NGF signaling. Here we solved by NMR the three-dimensional structure of the p75-TM-WT and the functionally inactive p75-TM-C257A dimers. Upon reconstitution in lipid micelles, p75-TM-WT forms the disulfide-linked dimers spontaneously. Under reducing conditions, p75-TM-WT is in a monomer-dimer equilibrium with the Cys(257) residue located on the dimer interface. In contrast, p75-TM-C257A forms dimers through the AXXXG motif on the opposite face of the α-helix. Biochemical and cross-linking experiments indicate that AXXXG motif is not on the dimer interface of p75-TM-WT, suggesting that the conformation of p75-TM-C257A may be not functionally relevant. However, rather than mediating p75 homodimerization, mutagenesis of the AXXXG motif reveals its functional role in the regulated intramembrane proteolysis of p75 catalyzed by the γ-secretase complex. Our structural data provide an insight into the key role of the Cys(257) in stabilization of the weak transmembrane dimer in a conformation required for the NGF signaling.


Subject(s)
Membrane Proteins/chemistry , Protein Domains , Protein Multimerization , Protein Structure, Secondary , Receptor, Nerve Growth Factor/chemistry , Amino Acid Motifs/genetics , Amino Acid Sequence , Blotting, Western , Cysteine/chemistry , Cysteine/genetics , Cysteine/metabolism , HeLa Cells , Humans , Lipids/chemistry , Magnetic Resonance Spectroscopy , Membrane Proteins/genetics , Membrane Proteins/metabolism , Micelles , Models, Molecular , Mutation , Oxidation-Reduction , Proteolysis , Receptor, Nerve Growth Factor/genetics , Receptor, Nerve Growth Factor/metabolism
7.
PLoS Biol ; 12(8): e1001918, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25093680

ABSTRACT

The p75 neurotrophin receptor, a member of the tumor necrosis factor receptor superfamily, is required as a co-receptor for the Nogo receptor (NgR) to mediate the activity of myelin-associated inhibitors such as Nogo, MAG, and OMgp. p45/NRH2/PLAIDD is a p75 homologue and contains a death domain (DD). Here we report that p45 markedly interferes with the function of p75 as a co-receptor for NgR. P45 forms heterodimers with p75 and thereby blocks RhoA activation and inhibition of neurite outgrowth induced by myelin-associated inhibitors. p45 binds p75 through both its transmembrane (TM) domain and DD. To understand the underlying mechanisms, we have determined the three-dimensional NMR solution structure of the intracellular domain of p45 and characterized its interaction with p75. We have identified the residues involved in such interaction by NMR and co-immunoprecipitation. The DD of p45 binds the DD of p75 by electrostatic interactions. In addition, previous reports suggested that Cys257 in the p75 TM domain is required for signaling. We found that the interaction of the cysteine 58 of p45 with the cysteine 257 of p75 within the TM domain is necessary for p45-p75 heterodimerization. These results suggest a mechanism involving both the TM domain and the DD of p45 to regulate p75-mediated signaling.


Subject(s)
Protein Multimerization , Receptor, Nerve Growth Factor/chemistry , Receptor, Nerve Growth Factor/metabolism , Receptors, Nerve Growth Factor/chemistry , Receptors, Nerve Growth Factor/metabolism , Signal Transduction , Amino Acid Sequence , Animals , Cysteine/metabolism , HEK293 Cells , Humans , Magnetic Resonance Spectroscopy , Mice , Models, Biological , Models, Molecular , Molecular Sequence Data , Protein Binding , Protein Interaction Mapping , Protein Stability , Receptors, Cell Surface/metabolism , Sciatic Nerve/injuries , Sciatic Nerve/metabolism , Solutions , Structure-Activity Relationship , Up-Regulation
8.
Neurobiol Aging ; 34(11): 2623-38, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23796660

ABSTRACT

Neurogenesis persists in the adult brain as a form of plasticity due to the existence of neural stem cells (NSCs). Alterations in neurogenesis have been found in transgenic Alzheimer's disease (AD) mouse models, but NSC activity and neurogenesis in sporadic AD models remains to be examined. We herein describe a remarkable increase in NSC proliferation in the forebrain of SAMP8, a non-transgenic mouse strain that recapitulates the transition from healthy aging to AD. The increase in proliferation is transient, precedes AD-like symptoms such as amyloid beta 1-42 [Aß(1-42)] increase or gliosis, and is followed by a steep decline at later stages. Interestingly, in vitro studies indicate that secreted Aß(1-42) and PI3K signaling may account for the early boost in NSC proliferation. Our results highlight the role of soluble Aß(1-42) peptide and PI3K in the autocrine regulation of NSCs, and further suggest that over-proliferation of NSCs before the appearance of AD pathology may underlie neurogenic failure during the age-related progression of the disease. These findings have implications for therapeutic approaches based on neurogenesis in AD.


Subject(s)
Adult Stem Cells/physiology , Aging/genetics , Aging/pathology , Amyloid beta-Peptides/pharmacology , Cell Proliferation/drug effects , Peptide Fragments/pharmacology , Adult Stem Cells/classification , Adult Stem Cells/drug effects , Age Factors , Amyloid beta-Peptides/metabolism , Animals , Antigens, CD1/metabolism , Brain/metabolism , Brain/pathology , Bromodeoxyuridine , Cells, Cultured , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Glial Fibrillary Acidic Protein/metabolism , Lateral Ventricles/cytology , Male , Mice , Mice, Inbred ICR , Mice, Mutant Strains , Peptide Fragments/metabolism , Phosphatidylinositol 3-Kinases/metabolism , SOXB1 Transcription Factors/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics
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