Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8+ T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness

Wu, Jingxia; Ma, Shaolin; Sandhoff, Roger; Ming, Yanan; Hotz‐Wagenblatt, Agnes; Timmerman, Vincent; Bonello‐Palot, Nathalie; Schlotter‐Weigel, Beate; Auer‐Grumbach, Michaela; Seeman, Pavel; Löscher, Wolfgang N.; Reindl, Markus; Weiß, Florian; Mah, Eric Y.; Weisshaar, Nina; Madi, Alaa; Möhr, Kerstin; Schlimbach, Tilo; Cárdenas, Rubí M.-H. Velasco; Koeppel, Jonas; Grünschläger, Florian; Müller, Lisann; Baumeister, Maren; Brügger, Britta; Schmitt, Michael; Wabnitz, Guido H.; Samstag, Yvonne; Cui, Guoliang

doi:10.1016/j.immuni.2019.03.005

Cited by 34 publications

(31 citation statements)

References 75 publications

(86 reference statements)

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“…In animal models of hereditary sensory and autonomic neuropathy type 1 (HSAN1), ectopic expression of dominant-negative variants of the Drosophila and C. elegans Spt1 gene caused dysregulated vesicle trafficking (Cui et al, 2019;Oswald et al, 2015). In addition, a mouse model of HSAN1 with ablation of Sptlc2 manifested significant ER stress and prolonged activation of mTORC1 (Wu et al, 2019). Downstream of SPTLC1/2, deficiencies in ceramide synthase 1 and 2 caused progressive myoclonic epilepsy (Godeiro Junior et al, 2018;Mosbech et al, 2014;Vanni et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress

Tzou

Lin

et al. 2021

Cell Reports

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Section: Discussionmentioning

confidence: 99%

Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress

Tzou

Lin

et al. 2021

Cell Reports

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“…The normally robust CD8 + effector T cell response to LCMV was severely impaired with SPTLC2deficiency due to decreased metabolic fitness and increased cell death, attributed to prolonged mTORC1 activation and increased ER stress. Remarkably, these defects in SPTLC2deficient murine T cells and HSAN-I patient T cells were rescued by supplementation of sphingolipids in culture (48).…”

Section: Ormdl3 and T Cell Metabolic Fitnessmentioning

confidence: 97%

ORMDL3 and Asthma: Linking Sphingolipid Regulation to Altered T Cell Function

2020

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Orosomucoid like 3 (ORMDL3) encodes an ER-resident transmembrane protein that regulates the activity of serine palmitoyltransferase (SPT), the first and rate-limiting enzyme for sphingolipid biosynthesis in cells. A decade ago, several genome wide association studies revealed single nucleotide polymorphisms associated with increased ORMDL3 protein expression and susceptibility to allergic asthma. Since that time, numerous studies have investigated how altered ORMDL3 expression might predispose to asthma and other autoimmune/inflammatory diseases. In this brief review, we focus on growing evidence suggesting that heightened ORMDL3 expression specifically in CD4+ T lymphocytes, the central orchestrators of adaptive immunity, constitutes a major underlying mechanism of asthma pathogenesis by skewing their differentiation and function. Furthermore, we explore how sphingolipid modulation in T cells might be responsible for these effects, and how further studies may interrogate this intriguing hypothesis.

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“…ER stress has been linked to CD8 + T-cell metabolic regulation and fitness in several disease settings (68,69). Indeed, mitochondrial function is essential for the CD8 + T cells (68).…”

Section: Cd8 + T Cellsmentioning

confidence: 99%

The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities

Song

Riesenberg

et al. 2020

Front. Immunol.

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The endoplasmic reticulum (ER) is an organelle equipped with mechanisms for proper protein folding, trafficking, and degradation to maintain protein homeostasis in the secretory pathway. As a defense mechanism, perturbation of ER proteostasis by ER stress agents activates a cascade of signaling pathways from the ER to the nucleus known as unfolded protein response (UPR). The primary goal of UPR is to induce transcriptional and translational programs to restore ER homeostasis for cell survival. As such, defects in UPR signaling have been implicated as a key contributor to multiple diseases including metabolic diseases, degenerative diseases, inflammatory disorders, and cancer. Growing evidence support the critical role of ER stress in regulating the fate as well as the magnitude of the immune response. Moreover, the availability of multiple UPR pharmacological inhibitors raises the hope that targeting UPR can be a new strategy for immune modulation and immunotherapy of diseases. This paper reviews the principal mechanisms by which ER stress affects immune cell biology and function, with a focus of discussion on UPR-associated immunopathology and the development of potential ER stress-targeted therapeutics.Frontiers in Immunology | www.frontiersin.org Conflict of Interest: ZL serves as member of scientific advisory board for Alphamab and Henlius Biotech and has a sponsored research agreement with Bristol-Myers Squibb.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8+ T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness

Cited by 34 publications

References 75 publications

Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress

Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress

ORMDL3 and Asthma: Linking Sphingolipid Regulation to Altered T Cell Function

The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities

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