REGγ controls Th17 cell differentiation and autoimmune inflammation by regulating dendritic cells

Zhou, Lei; Yao, Liangfang; Zhang, Qing; Xie, Wei; Wang, Xiaoshuang; Zhang, Huihui; Xu, Jinjin; Lin, Qingxia; Li, Qing; Yang, Xuan; Ji, Lei; Wang, Lu; Wang, Weicang; Wang, Weichao; Shi, Tingting; Fang, Lei; Zheng, Biao; Li, Lei; Liu, Shuang; Zhang, Bianhong; Li, Xiaotao

doi:10.1038/s41423-019-0287-0

Cited by 20 publications

(11 citation statements)

References 52 publications

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“…It is predominantly localized to the nucleus and downregulates many tumor suppressors, including p53 [ 10 ], p21 [ 11 ], p14 [ 12 ], p16 [ 12 ], Lats1 [ 13 ], PP2Ac [ 14 ], IκBε [ 15 ], and Smad7 [ 16 , 17 ], indicating its oncogenic properties. Factors involved in immune responses are also found as REGγ targets, including signal transducer and activator of transcription 3 (Stat3) [ 14 ], activation-induced deaminase (AID) [ 18 ], interferon regulatory factor 8 (IRF8) [ 19 ], and Oct-1 [ 20 ]. Likewise, some key proteins involved in metabolism that are also degraded by REGγ include SirT1 [ 21 ], SirT7 [ 22 ], and protein kinase A (PKA) [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Regulation of Life & Death by REGγ

Funderburk

Kang

2022

Cells

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REGγ, a proteasome activator belonging to the 11S (otherwise known as REG, PA28, or PSME) proteasome activator family, is widely present in many eukaryotes. By binding to the 20S catalytic core particle, REGγ acts as a molecular sieve to selectively target proteins for degradation in an ATP- and ubiquitin-independent manner. This non-canonical proteasome pathway directly regulates seemingly unrelated cellular processes including cell growth and proliferation, apoptosis, DNA damage response, immune response, and metabolism. By affecting different pathways, REGγ plays a vital role in the regulation of cellular life and death through the maintenance of protein homeostasis. As a promoter of cellular growth and a key regulator of several tumor suppressors, many recent studies have linked REGγ overexpression with tumor formation and suggested the REGγ-proteasome as a potential target of new cancer-drug development. This review will present an overview of the major functions of REGγ as it relates to the regulation of cellular life and death, along with new mechanistic insights into the regulation of REGγ.

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Section: Introductionmentioning

confidence: 99%

Regulation of Life & Death by REGγ

Funderburk

Kang

2022

Cells

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“…Although a recent report by Zhou et al . has recently studied REGγ/ PA28γ/ Psme3 in the context of EAE, the gene of interest in that study was not the antimicrobial Reg3ɣ, but encoded a proteasomal protein [61]. Therefore, to our knowledge Reg3γ has not been investigated in the context EAE.…”

Section: Discussionmentioning

confidence: 99%

Temporal overexpression of IL‐22 and Reg3γ differentially impacts the severity of experimental autoimmune encephalomyelitis

et al. 2021

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IL‐22 is an alpha‐helical cytokine which belongs to the IL‐10 family of cytokines. IL‐22 is produced by RORγt+ innate and adaptive lymphocytes, including ILC3, γδ T, iNKT, Th17 and Th22 cells and some granulocytes. IL‐22 receptor is expressed primarily by non‐haematopoietic cells. IL‐22 is critical for barrier immunity at the mucosal surfaces in the steady state and during infection. Although IL‐22 knockout mice were previously shown to develop experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), how temporal IL‐22 manipulation in adult mice would affect EAE course has not been studied previously. In this study, we overexpressed IL‐22 via hydrodynamic gene delivery or blocked it via neutralizing antibodies in C57BL/6 mice to explore the therapeutic impact of IL‐22 modulation on the EAE course. IL‐22 overexpression significantly decreased EAE scores and demyelination, and reduced infiltration of IFN‐γ+IL‐17A+Th17 cells into the central nervous system (CNS). The neutralization of IL‐22 did not alter the EAE pathology significantly. We show that IL‐22‐mediated protection is independent of Reg3γ, an epithelial cell‐derived antimicrobial peptide induced by IL‐22. Thus, overexpression of Reg3γ significantly exacerbated EAE scores, demyelination and infiltration of IFN‐γ+IL‐17A+ and IL‐17A+GM‐CSF+Th17 cells to CNS. We also show that Reg3γ may inhibit IL‐2‐mediated STAT5 signalling and impair expansion of Treg cells in vivo and in vitro. Finally, Reg3γ overexpression dramatically impacted intestinal microbiota during EAE. Our results provide novel insight into the role of IL‐22 and IL‐22‐induced antimicrobial peptide Reg3γ in the pathogenesis of CNS inflammation in a murine model of MS.

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“…In fact, elevated cellular levels of IRF8 resulting from the knockout of the PA28γ gene was found to lead to an increased release of transforming growth factor-β1 (TGF-β1) by DCs. The higher levels of secretion of this cytokine (and also interleukin 6) by DCs causes, in turn, an augmented polarization of interleukin-17A-producing CD4 + T cells (Th17), and the onset of an experimental autoimmune encephalomyelitis (EAE) in a mouse model [136]. Moreover, PA28γ was also reported to properly regulate immunoglobulin class switching that initiates antibody gene diversification in activated B lymphocytes by targeting the activation-induced deaminase (AID) for proteasomal degradation [137].…”

Section: Role In Immune Responsesmentioning

confidence: 99%

PA28γ: New Insights on an Ancient Proteasome Activator

Cascio

2021

Biomolecules

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PA28 (also known as 11S, REG or PSME) is a family of proteasome regulators whose members are widely present in many of the eukaryotic supergroups. In jawed vertebrates they are represented by three paralogs, PA28α, PA28β, and PA28γ, which assemble as heptameric hetero (PA28αβ) or homo (PA28γ) rings on one or both extremities of the 20S proteasome cylindrical structure. While they share high sequence and structural similarities, the three isoforms significantly differ in terms of their biochemical and biological properties. In fact, PA28α and PA28β seem to have appeared more recently and to have evolved very rapidly to perform new functions that are specifically aimed at optimizing the process of MHC class I antigen presentation. In line with this, PA28αβ favors release of peptide products by proteasomes and is particularly suited to support adaptive immune responses without, however, affecting hydrolysis rates of protein substrates. On the contrary, PA28γ seems to be a slow-evolving gene that is most similar to the common ancestor of the PA28 activators family, and very likely retains its original functions. Notably, PA28γ has a prevalent nuclear localization and is involved in the regulation of several essential cellular processes including cell growth and proliferation, apoptosis, chromatin structure and organization, and response to DNA damage. In striking contrast with the activity of PA28αβ, most of these diverse biological functions of PA28γ seem to depend on its ability to markedly enhance degradation rates of regulatory protein by 20S proteasome. The present review will focus on the molecular mechanisms and biochemical properties of PA28γ, which are likely to account for its various and complex biological functions and highlight the common features with the PA28αβ paralog.

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REGγ controls Th17 cell differentiation and autoimmune inflammation by regulating dendritic cells

Cited by 20 publications

References 52 publications

Regulation of Life & Death by REGγ

Regulation of Life & Death by REGγ

Temporal overexpression of IL‐22 and Reg3γ differentially impacts the severity of experimental autoimmune encephalomyelitis

PA28γ: New Insights on an Ancient Proteasome Activator

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