Role of Proteasomes in Inflammation

Goetzke, Carl Christoph; Ebstein, Frédéric; Kallinich, Tilmann

doi:10.3390/jcm10081783

Cited by 49 publications

(36 citation statements)

References 189 publications

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“…While activation and upregulation of the UPS contributes essentially to skeletal muscle atrophy as discussed in the previous paragraphs, proteasome dysfunction also promotes muscle weakness in contrast to that. Muscle atrophy, myositis, lipodystrophy, arthritis, recurrent episodes of fever and skin eruptions in patients are typical features in all forms of Proteasome-Associated Autoinflammatory Syndrome (PRAAS), which is represented by sterile inflammation [ 392 ]. Several names were used by different groups to describe this disease spectrum [ 393 ].…”

Section: Role Of Proinflammatory Cytokines In Inflammation-induced Muscle Wastingmentioning

confidence: 99%

“…By now, it is clear that not all discovered proteasome loss-of-function mutations cause severe autoinflammation. Genomic alterations in genes of 19S subunits ( PSMD12 [ 401 ], PSMC3 [ 402 ]) or in PSMB1 encoding β6 [ 403 ] are predominantly characterized by neurodevelopmental disorders and do not present with pronounced autoinflammation [ 47 , 392 ]. In addition to type I IFN, PRAAS patients present with moderate-to-strongly increased serum levels of IL-6 [ 393 , 404 ].…”

Section: Role Of Proinflammatory Cytokines In Inflammation-induced Muscle Wastingmentioning

confidence: 99%

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Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation

2021

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The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein homeostasis with increased protein degradation and decreased protein synthesis, eventually causing a decrease in muscle structural proteins. The ubiquitin proteasome system (UPS) is the predominant protein-degrading system in muscle that is activated during diverse muscle atrophy conditions, e.g., inflammation. The specificity of UPS-mediated protein degradation is assured by E3 ubiquitin ligases, such as atrogin-1 and MuRF1, which target structural and contractile proteins, proteins involved in energy metabolism and transcription factors for UPS-dependent degradation. Although the regulation of activity and function of E3 ubiquitin ligases in inflammation-induced muscle atrophy is well perceived, the contribution of the proteasome to muscle atrophy during inflammation is still elusive. During inflammation, a shift from standard- to immunoproteasome was described; however, to which extent this contributes to muscle wasting and whether this changes targeting of specific muscular proteins is not well described. This review summarizes the function of the main proinflammatory cytokines and acute phase response proteins and their signaling pathways in inflammation-induced muscle atrophy with a focus on UPS-mediated protein degradation in muscle during sepsis. The regulation and target-specificity of the main E3 ubiquitin ligases in muscle atrophy and their mode of action on myofibrillar proteins will be reported. The function of the standard- and immunoproteasome in inflammation-induced muscle atrophy will be described and the effects of proteasome-inhibitors as treatment strategies will be discussed.

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Section: Role Of Proinflammatory Cytokines In Inflammation-induced Muscle Wastingmentioning

confidence: 99%

Section: Role Of Proinflammatory Cytokines In Inflammation-induced Muscle Wastingmentioning

confidence: 99%

Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation

2021

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“…A majority of intracellular proteins are modified by ubiquitination ( Amm et al, 2014 ). Several Ub signals are recognized by proteasomes, thereby serving as a regulatory mechanism for protein degradation, affecting nearly all aspects of cellular processes ( Chowdhury and Enenkel, 2015 ; Hanna et al, 2019 ; Sakai et al, 2020 ; Fhu and Ali, 2021 ; Goetzke et al, 2021 ; Qu et al, 2021 ; Zou and Lin, 2021 ). Ubiquitin signaling is strictly regulated by a multistep cascade reaction consisting of three enzyme groups.…”

Section: Introductionmentioning

confidence: 99%

Functions and Molecular Mechanisms of Deltex Family Ubiquitin E3 Ligases in Development and Disease

Wang

Sun

et al. 2021

Front. Cell Dev. Biol.

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Ubiquitination is a posttranslational modification of proteins that significantly affects protein stability and function. The specificity of substrate recognition is determined by ubiquitin E3 ligase during ubiquitination. Human Deltex (DTX) protein family, which functions as ubiquitin E3 ligases, comprises five members, namely, DTX1, DTX2, DTX3, DTX3L, and DTX4. The characteristics and functional diversity of the DTX family proteins have attracted significant attention over the last decade. DTX proteins have several physiological and pathological roles and are closely associated with cell signal transduction, growth, differentiation, and apoptosis, as well as the occurrence and development of various tumors. Although they have been extensively studied in various species, data on structural features, biological functions, and potential mechanisms of action of the DTX family proteins remain limited. In this review, recent research progress on each member of the DTX family is summarized, providing insights into future research directions and potential strategies in disease diagnosis and therapy.

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“…Clearly, the divergence between the two diseases is not dictated by the location of the affected subunit within the 26S proteasome, as initially assumed ( Ebstein et al, 2019 ). The notion that CANDLE/PRAAS develop peripheral autoimmunity is not unexpected given the pleiotropic role of proteasomes in multiple inflammatory signal cascades ( Cetin et al, 2021 ; Goetzke et al, 2021 ). On the contrary, the lack of systemic manifestations in NDD due to proteasome loss-of-function mutations is intriguing, but again does not necessarily imply the absence of autoinflammation in some tissues and/or the generation of atypical inflammatory signatures that may have been overlooked.…”

Section: Ndd-associated E3 Ubiquitin Ligases and Their Roles In The Immune Responsementioning

confidence: 99%

Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

Ebstein

Küry

Papendorf

et al. 2021

Front. Mol. Neurosci.

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Over thirty years have passed since the first description of ubiquitin-positive structures in the brain of patients suffering from Alzheimer’s disease. Meanwhile, the intracellular accumulation of ubiquitin-modified insoluble protein aggregates has become an indisputable hallmark of neurodegeneration. However, the role of ubiquitin and a fortiori the ubiquitin-proteasome system (UPS) in the pathogenesis of neurodevelopmental disorders (NDD) is much less described. In this article, we review all reported monogenic forms of NDD caused by lesions in genes coding for any component of the UPS including ubiquitin-activating (E1), -conjugating (E2) enzymes, ubiquitin ligases (E3), ubiquitin hydrolases, and ubiquitin-like modifiers as well as proteasome subunits. Strikingly, our analysis revealed that a vast majority of these proteins have a described function in the negative regulation of the innate immune response. In this work, we hypothesize a possible involvement of autoinflammation in NDD pathogenesis. Herein, we discuss the parallels between immune dysregulation and neurodevelopment with the aim at improving our understanding the biology of NDD and providing knowledge required for the design of novel therapeutic strategies.

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Role of Proteasomes in Inflammation

Cited by 49 publications

References 189 publications

Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation

Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation

Functions and Molecular Mechanisms of Deltex Family Ubiquitin E3 Ligases in Development and Disease

Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

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