A Sentinel in the Crosstalk Between the Nervous and Immune System: The (Immuno)-Proteasome

Limanaqi, Fiona; Biagioni, Francesca; Gaglione, Anderson; Busceti, Carla Letizia

doi:10.3389/fimmu.2019.00628

Cited by 51 publications

(67 citation statements)

References 152 publications

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“…In this scenario, mTOR inhibition represents a potential strategy to enhance both autophagy and UPS-dependent protein degradation. The mTOR pathway also regulates the switch between standard and inflammation-inducible UPS subunits forming the immunoproteasome, which is implicated in antigen-peptide processing [104][105][106]. Nonetheless, besides empowering protein degradation, the shuttling of UPS within autophagy vacuoles, which is mediated by p62, may also represent a mechanism aimed at clearing inactive UPS subunits themselves [65,107].…”

Section: Emerging Mechanisms Underlying Autophagy and Proteasome Crosmentioning

confidence: 99%

“…The immunoproteasome is an alternative UPS isoform implicated in antigen (Ag) processing and presentation, which operates constitutively in immune cells while being induced by pro-inflammatory and oxidative stimuli in almost any other cell type [104][105][106][205][206][207][208][209][210][211]. In fact, the immunoproteasome is significantly upregulated in reactive astrocytes, microglia, and neurons in both patients and experimental models of neurodegeneration [104][105][106][205][206][207][208][209][210][211][212][213]. Compared with standard proteasome, the immunoproteasome owns enhanced chymotrypsin-like activity and structural peculiarities which enable fast and efficient processing of endogenous, microbial-and misfold/aggregation-prone-proteins [104,[206][207][208].…”

Section: Protein Glycation and Cell-clearing Systems Alterations Bridmentioning

confidence: 99%

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Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

Limanaqi

Biagioni

Gambardella

et al. 2020

IJMS

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Alterations in autophagy and the ubiquitin proteasome system (UPS) are commonly implicated in protein aggregation and toxicity which manifest in a number of neurological disorders. In fact, both UPS and autophagy alterations are bound to the aggregation, spreading and toxicity of the so-called prionoid proteins, including alpha synuclein (α-syn), amyloid-beta (Aβ), tau, huntingtin, superoxide dismutase-1 (SOD-1), TAR-DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS). Recent biochemical and morphological studies add to this scenario, focusing on the coordinated, either synergistic or compensatory, interplay that occurs between autophagy and the UPS. In fact, a number of biochemical pathways such as mammalian target of rapamycin (mTOR), transcription factor EB (TFEB), Bcl2-associated athanogene 1/3 (BAG3/1) and glycogen synthase kinase beta (GSk3β), which are widely explored as potential targets in neurodegenerative proteinopathies, operate at the crossroad between autophagy and UPS. These biochemical steps are key in orchestrating the specificity and magnitude of the two degradation systems for effective protein homeostasis, while intermingling with intracellular secretory/trafficking and inflammatory pathways. The findings discussed in the present manuscript are supposed to add novel viewpoints which may further enrich our insight on the complex interactions occurring between cell-clearing systems, protein misfolding and propagation. Discovering novel mechanisms enabling a cross-talk between the UPS and autophagy is expected to provide novel potential molecular targets in proteinopathies.

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Section: Emerging Mechanisms Underlying Autophagy and Proteasome Crosmentioning

confidence: 99%

Section: Protein Glycation and Cell-clearing Systems Alterations Bridmentioning

confidence: 99%

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

Limanaqi

Biagioni

Gambardella

et al. 2020

IJMS

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“…In several neurodegenerative diseases, the iP is known to clear reactive oxygen species (ROS) and degrade poly-ubiquitinated proteins (62-64); and, there is evidence that the iP may be dysregulated during MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS (64-66). Additionally, astrocytes have been implicated in modulating neuroinflammation and neurodegeneration (67-69); however, the role of the astrocyte iP during MS and EAE has not yet been fully elucidated.…”

Section: Resultsmentioning

confidence: 99%

Regional astrocyte interferon-γ signaling regulates immunoproteasome-mediated protection during chronic autoimmunity

Sinyuk

et al. 2019

Preprint

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17In early autoimmune neuroinflammation, interferon (IFN)g and its upregulation of the 18 immunoproteasome (iP) is pathologic. However, during chronic multiple sclerosis (MS), IFNg has 19 protective properties and, the role of the iP remains to be fully elucidated. Here, we demonstrated 20 that IFNg signaling in regional astrocytes induces the iP and protects the CNS during 21 autoimmunity. In MS tissue, iP expression was enhanced in spinal cord compared to brainstem 22 lesions, which correlated with a decrease in oxidative stress. In vitro, IFNg stimulation enhanced 23 iP expression, reduced reactive oxygen species burden, and decreased oxidatively damaged and 24 poly-ubiquitinated protein accumulation preferentially in human spinal cord astrocytes, which was 25 abrogated with the use of the iP inhibitor, ONX 0914. During the chronic phase of an MS animal 26 model, experimental autoimmune encephalomyelitis (EAE), ONX 0914 treatment exacerbated 27 disease and led to increased oxidative stress and poly-ubiquitinated protein build-up. Finally, mice 28 with astrocyte-specific loss of the IFNg receptor exhibited worsened chronic EAE associated with 29 reduced iP expression, enhanced lesion size and oxidative stress and poly-ubiquitinated protein 30 accumulation in astrocytes. Taken together, our data reveal a protective role for IFNg in chronic 31 neuroinflammation and identify a novel function of the iP in astrocytes during CNS autoimmunity. 32 33 34 Multiple sclerosis (MS) is the most common chronic inflammatory and 35 neurodegenerative disease of the central nervous system (CNS) (1). During the 36 pathogenesis of MS, there is immune cell infiltration, demyelination, and reactive gliosis 37within CNS lesions in multiple regions (2). Relapsing-remitting MS (RRMS) is a subtype 38 that affects approximately 85% of patients and is characterized by episodic periods of 39 neurological dysfunction, often associated with inflammation, followed by partial or 40 complete recovery. A significant proportion of these patients go on to develop secondary 41 progressive MS (SPMS), during which they have fewer remissions and increasing 42 atrophy, correlating with progressive disability (3, 4). Primary progressive (PPMS) a third 43 subtype of MS, affects approximately 15% of patients and is associated with continuous, 44 progressive loss of neurological function after initial diagnosis, without periods of 45 remission (5, 6). Of note, it is thought that the pathology associated with RRMS has a 46 relatively significant inflammatory component, while in SPMS and PPMS, inflammation is 47 an animal model of MS, astrocytes are known to exhibit regional heterogeneity in gene 58 expression and response to inflammation (17)(18)(19). Indeed, ablation of astrocytes following 59 several types of CNS injury leads to sustained inflammation, impaired repair, and 60 increased neurodegeneration (20-29), suggesting that a diverse astrocytic response is 61 critical in healthy tissue preservation and support, minimizing CNS bystander damage 62 during...

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“…The core machinery of the UPS, the 26S proteasome, is composed of β catalytic subunits existing as either constitutive or inducible isoforms. During inflammation or oxidative stress, the constitutive subunits of the P26S are replaced by their inducible counterparts, leading to the formation of the immunoproteasome, which is endowed with pathophysiological functions related to immunity and inflammation [35]. mTOR hyperactivation has been linked with downregulation of constitutive proteasome subunits and subsequent induction of immunoproteasome.…”

Section: A Glance At Mtor-related Ups Alterations In Epilepsymentioning

confidence: 99%

“…Still in this context, it is worth mentioning that beyond autophagy, the ubiquitin-proteasome system (UPS), which regulates neuron excitability, synaptic plasticity, and neuro-inflammation/immunity, is altered in epilepsy as well [34][35][36][37]. It is remarkable that, similar to autophagy failure, UPS alterations in epilepsy are bound to mTOR hyperactivation [37].…”

Section: Introductionmentioning

confidence: 99%

mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update

Limanaqi

Biagioni

Busceti

et al. 2020

IJMS

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Recent evidence suggests that autophagy impairment is implicated in the epileptogenic mechanisms downstream of mTOR hyperactivation. This holds true for a variety of genetic and acquired epileptic syndromes besides malformations of cortical development which are classically known as mTORopathies. Autophagy suppression is sufficient to induce epilepsy in experimental models, while rescuing autophagy prevents epileptogenesis, improves behavioral alterations, and provides neuroprotection in seizure-induced neuronal damage. The implication of autophagy in epileptogenesis and maturation phenomena related to seizure activity is supported by evidence indicating that autophagy is involved in the molecular mechanisms which are implicated in epilepsy. In general, mTOR-dependent autophagy regulates the proliferation and migration of inter-/neuronal cortical progenitors, synapse development, vesicular release, synaptic plasticity, and importantly, synaptic clustering of GABAA receptors and subsequent excitatory/inhibitory balance in the brain. Similar to autophagy, the ubiquitin–proteasome system is regulated downstream of mTOR, and it is implicated in epileptogenesis. Thus, mTOR-dependent cell-clearing systems are now taking center stage in the field of epilepsy. In the present review, we discuss such evidence in a variety of seizure-related disorders and models. This is expected to provide a deeper insight into the molecular mechanisms underlying seizure activity.

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A Sentinel in the Crosstalk Between the Nervous and Immune System: The (Immuno)-Proteasome

Cited by 51 publications

References 152 publications

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

Regional astrocyte interferon-γ signaling regulates immunoproteasome-mediated protection during chronic autoimmunity

mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update

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