GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis

Xia, Xichun; Cao, Guangchao; Sun, Guodong; Zhu, Leqing; Tian, Yixia; Song, Yueqi; Guo, Chengbin; Wang, Xiao; Zhong, Jingxiang; Zhou, Wei; Li, Peng; Zhang, Hua; Hao, Jianlei; Li, Zhizhong; Deng, Liehua; Yin, Zhinan; Gao, Yunfei

doi:10.1172/jci129269

Cited by 73 publications

(65 citation statements)

References 63 publications

(76 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, Xia and colleagues found that Glutaminase 1(GLS1)-mediated glutaminolysis was aberrantly activated in psoriasis patients, as indicated by elevated mRNA and protein levels in both immune cells and keratinocytes, contributing to the pathogenesis of psoriasis. In keratinocytes, induction of GLS1 was caused by IL-17A/MALT1/c-Jun axis, and enhanced cell proliferation and chemokine production, contributing to the development of psoriasis phenotype [ 66 ].…”

Section: Factors Regulating Psoriatic Keratinocytesmentioning

confidence: 99%

Advances in the pathogenesis of psoriasis: from keratinocyte perspective

et al. 2022

View full text Add to dashboard Cite

Psoriasis is a complex long-lasting inflammatory skin disease with high prevalence and associated comorbidity. It is characterized by epidermal hyperplasia and dermal infiltration of immune cells. Here, we review the role of keratinocytes in the pathogenesis of psoriasis, focusing on factors relevant to genetics, cytokines and receptors, metabolism, cell signaling, transcription factors, non-coding RNAs, antimicrobial peptides, and proteins with other different functions. The critical role of keratinocytes in initiating and maintaining the inflammatory state suggests the great significance of targeting keratinocytes for the treatment of psoriasis.

show abstract

Section: Factors Regulating Psoriatic Keratinocytesmentioning

confidence: 99%

Advances in the pathogenesis of psoriasis: from keratinocyte perspective

et al. 2022

View full text Add to dashboard Cite

show abstract

“…65,70 One of the mechanisms that may link altered histone acetylation in immune cells with psoriasis development involves GLS1-mediated glutaminolysis. 71 In this paper, GLS1 was shown to promote Th17 and γδ T17 differentiation through enhancement of H3K9Ac and H3K27Ac in the IL17A promoter region. 71 Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are two major groups of enzymes that are responsible for histone acetylation.…”

Section: Histone Methylationmentioning

confidence: 76%

“…71 In this paper, GLS1 was shown to promote Th17 and γδ T17 differentiation through enhancement of H3K9Ac and H3K27Ac in the IL17A promoter region. 71 Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are two major groups of enzymes that are responsible for histone acetylation. HDAC-1 has been shown to be upregulated in psoriatic skin.…”

Section: Histone Methylationmentioning

confidence: 76%

Dysregulated epigenetic modifications in psoriasis

Zeng

Tsoi

Gudjonsson

2021

Experimental Dermatology

View full text Add to dashboard Cite

The observed incidence of psoriasis has been gradually increasing over time (J Am Acad Dermatol, 03, 2009, 394), but the underlying pathogenic factors have remained unclear. Recent studies suggest the importance of epigenetic modification in the pathogenesis of psoriasis. Aberrant epigenetic patterns including changes in DNA methylation, histone modifications and non-coding RNA expression are observed in psoriatic skin. Reversing these epigenetic mechanisms has showed improvement in psoriatic phenotypes, making epigenetic therapy a potential avenue for psoriasis treatment. Here, we summarize relevant evidence for epigenetic dysregulation contributing to psoriasis susceptibility and pathogenesis, and the factors responsible for epigenetic modifications, providing directions for potential future clinical avenues.

show abstract

“…Here we show that the involvement of glutamine metabolism in psoriasis acts beyond the differentiation of Th17 cells and is also part of the mechanism whereby keratinocytes contribute to this disease. Based on the requirement for glutaminolysis in Th17 differentiation, Xia et al (Xia et al, 2020) also described the potential of GLS inhibition in the treatment of psoriasis. However, there it was suggested that the effect on psoriasis was due to GLS inhibition in T cells and consequent reduced Th17 differentiation.…”

Section: Discussionmentioning

confidence: 99%

Hsa-miR-31-5p controls a metabolic switch in psoriatic keratinocytes that identifies therapeutic intervention

Wang

Yue

Vos

et al. 2022

Preprint

View full text Add to dashboard Cite

Psoriasis is characterized by a combination of keratinocyte hyperproliferation and immune cell activation. Immune cell activation requires increased glucose consumption, consequently limiting glucose availability for other cell types like keratinocytes. In psoriasis Hsa-microRNA-31-5p (miR-31) is highly expressed in keratinocytes. Here we show that miR-31 expression in keratinocytes is induced by limited glucose availability and increases survival under limiting glucose conditions, by increasing glutamine metabolism. In addition, miR-31 induced glutamine metabolism results in secretion of specific metabolites (aspartate and glutamate) but also immuno-modulatory factors. We show that this miR-31-induced secretory phenotype is sufficient to induce Th17 cell differentiation, a hallmark of psoriasis. Inhibition of glutaminase (GLS) using CB-839 impedes miR31-induced metabolic rewiring and secretion of immuno-modulatory factors. Concordantly, pharmacological targeting of GLS alleviated psoriasis pathology in a mouse model of psoriasis. Together our data illustrate an emerging concept of metabolic interaction across cell compartments that characterizes disease development, which can be employed to design effective treatment options for disease, as shown here for psoriasis.

show abstract

GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis

Cited by 73 publications

References 63 publications

Advances in the pathogenesis of psoriasis: from keratinocyte perspective

Advances in the pathogenesis of psoriasis: from keratinocyte perspective

Dysregulated epigenetic modifications in psoriasis

Hsa-miR-31-5p controls a metabolic switch in psoriatic keratinocytes that identifies therapeutic intervention

Contact Info

Product

Resources

About