Control of B lymphocyte development and functions by the mTOR signaling pathways

Iwata, Terri; Ramírez-Komo, Julita A.; Park, Heon; Iritani, Brian M.

doi:10.1016/j.cytogfr.2017.04.005

Cited by 43 publications

(51 citation statements)

References 148 publications

(181 reference statements)

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“…Other pathways included modulators of metabolism and mitochondria. In mature B cells, the ERK5 signaling pathway, which is indispensable for BAFFinduced mature B cell survival and self-reactivity, was affected (53,54), as well as the mechanistic target of rapamycin (mTOR) and transforming growth factor (TGF)-b signaling pathways (55,56). Together, the large number of affected pathways suggests compound effects of mutant proteomes in the absence of SRPK3.…”

Section: Discussionmentioning

confidence: 99%

SRPK3 regulates alternative pre-mRNA splicing required for B lymphocyte development and humoral responsiveness

Arends

Taliaferro

Peterman

et al. 2019

Preprint

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One Sentence Summary: SRPK3 regulates alternative splicing of pre-mRNA that is crucial for B cell development, activation and antibody responses. Abstract:Alternative splicing (AS) of pre-mRNA is a critical component of transcriptional regulation that diversifies the cellular proteome. The Serine-Arginine Protein Kinases (SRPK) initiate early events in AS. Using conditional knockout mice (cKO), we demonstrated the importance of the X-linked gene Srpk3 in B lymphocyte development and in response to immunization in vivo.Significantly decreased numbers of immature and mature B cells were observed in Srpk3-cKO BM relative to wild-type (WT). Immunization of Srpk3-cKO mice with a T lymphocyteindependent type-2 antigen elicited greatly reduced amounts of specific IgG3. Srpk3 deletion resulted in hundreds of differentially spliced mRNAs in B cells, including mRNAs encoding proteins associated with signaling pathways and mitochondrial function. Several alternative splicing outcomes in Srpk3-cKO cells are due to altered splicing regulation of SR proteins. We conclude that Srpk3 is an immunomodulatory kinase that controls humoral immunity via its regulation of pre-mRNA splicing, antibody production, and metabolism in B cells. Introduction:Co-transcriptional mechanisms of gene regulation are emerging as important contributors to immune cell differentiation and function. One such mechanism is alternative pre-mRNA splicing (AS), which increases informational diversity, functional capacity, and the efficiency of protein expression (1). Recent studies have confirmed that AS influences immunity and tolerance through its roles in lymphocyte homeostasis (2). Additionally, B cell differentiation, activation, and maturation to antigen secreting cells (ASCs) are dependent on unique splicing patterns that modulate B cell responsiveness and function (3,4). Therefore, understanding how pre-mRNA splicing is regulated in these cells is of critical importance.The functional spliceosome is a dynamic machine comprised of approximately 20 protein and RNA components that regulate splice site selection in pre-mRNAs concurrently with transcription (5, 6). Upstream regulators of splicing include the Serine-Arginine Protein Kinase (SRPK) family, a group of highly conserved serine-threonine kinases that phosphorylate Serine-Arginine repeat (SR)-rich proteins in response to extracellular signals (7-10). SR proteins include splicing factors (SRSF1-12) that promote splice site selection by bridging between initial splice site selection in the pre-spliceosome and assembly of the mature spliceosome.In mammals, SRPK proteins (SRPK1 and SRPK2) have been extensively studied as regulators of AS and mRNA maturation (11-13), transduction of growth signaling (14), chromatin reorganization (15), cell cycle (7) and metabolic signaling (16). However, the function of SRPK3 has not been elucidated. SRPK3 was identified first as a transcriptional target of Myocyte Enhancer Factor 2C (MEF2C) in skeletal muscle and the heart (17). Later studies identified the X-linked ...

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Section: Discussionmentioning

confidence: 99%

SRPK3 regulates alternative pre-mRNA splicing required for B lymphocyte development and humoral responsiveness

Arends

Taliaferro

Peterman

et al. 2019

Preprint

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“…6 As shown in Fig. 6, the expression of mTOR was seemed to increase in PBM treatment group over 660 nm, but not significantly.…”

Section: The Pbm Effect On Mtor Expression Of Hce-t Corneal Epitheliamentioning

confidence: 91%

“…mTORC2, by comparison, is more specifically activated by growth factor signaling, and facilitates cell survival and cytoskeletal reorganization to promote cell migration and adhesion. 6,23 In addition, the Rho-GTPase family has been known to the target of mTORC2 kinases. 6 Unlike what we expected, the expression of mTORC2 was significantly decreased after PBM treatment at 470 and 530 nm, and not increased by PBM treatment over 660 nm (Fig.…”

Section: Discussionmentioning

confidence: 99%

Effect of Photobiomodulation on Wound Healing of the Corneal Epithelium through Rho-GTPase

et al. 2017

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Background and ObjectivesIn recent years, photobiomodulation (PBM) using low-level light has been applied to diverse clinical approaches because of its potential to elevate the cell metabolism or regulate various signaling pathways. This study evaluated the possibility of a short term effect of PBM on the wound healing of corneal epithelial cells. Rapid healing of the corneal epithelium and the return of an intact basement membrane can restore the eye's normal mechanical barriers. The migration, proliferation, attachment, and cytoskeletal rearrangement play a critical role in the wound healing process of the corneal epithelium. Materials and MethodsTo determine which wavelength was most effective on corneal epithelium wound healing, light emitting diode (LED) arrays with wavelengths of 470, 530, 660, 740, and 850 nm were used. The proliferative effect was assessed using a MTT assay, cell cycle assay, and BrdU immunofluorescence (IF) staining, and the motility effect was examined using a wound healing assay after PBM. The cytoskeletal rearrangement effect of PBM was also evaluated by Western blot analysis and IF staining.Results PBM had no effect on cell proliferation; the cell cycle portion and BrdU were not changed after the PBM treatment, whereas cell survival was decreased at 470 nm. On the other hand, PBM at wavelengths greater than 660 nm affected migration. In particular, 740 nm was the most effective. The expression of Rho A and Rho C increased after PBM at wavelengths greater than 660 nm. The levels of cdc42 and mTORC2 expression were similar. ConclusionThis study showed that PBM could increase the corneal epithelial cell migration capacity without cell proliferation in a short time via the activation of a part of Rho-GTPase pathways without the effect of the upstream signals. These findings may be used for the future development of PBM-based therapy for acute ocular surface diseases. Key words

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“…RagA and RagC together with other molecules form a supercomplex at the surface of lysosomes that recruits and activates mTORC1 under nutrient sufficiency. 67 Constitutively active RagA renders mTORC1 signaling independent of the presence of amino acids and has been shown to reduce B cell competitiveness in the GC 56 (Figure 2). In contrast, expression of mutant alleles of the gene RagC that drive partial but not complete uncoupling of mTORC1 activity from amino acid dependence has been shown to boost GC expansion 68 (Figure 2).…”

Section: Me Taboli C Bal An Ce In Ac Tivated and G Erminal Center Bmentioning

confidence: 99%

The role of metabolic checkpoint regulators in B cell survival and transformation

Jellusova

2020

Immunological Reviews

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In response to mitogenic stimulation, B cells activate different pro-anabolic signaling pathways such as c-Myc-and mTORC1-dependent networks to satisfy the energetic demands of biomass synthesis and proliferation. In order to preserve viability and function, cell growth cannot progress unchecked and must be adjusted according to the availability of nutrients. Nutrient-sensing proteins such as AMPK antagonize mTORC1 activity in response to starvation. If pro-anabolic signaling pathways are aberrantly activated, B cells may lack the metabolic capacity to accommodate their energetic needs, which can lead to cell death. On the other hand, metabolic hyperactivation is a salient feature of cancer cells, suggesting that mechanisms exist, which allow B cells to cope with metabolic stress. The aim of this review is to discuss how B cells respond to a mismatch between energy supply and demand and what the consequences are of metabolic dysregulation in normal and malignant B cells. K E Y W O R D Sanabolism, autophagy, B cells, metabolic stress, mTORC1, senescence

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Control of B lymphocyte development and functions by the mTOR signaling pathways

Cited by 43 publications

References 148 publications

SRPK3 regulates alternative pre-mRNA splicing required for B lymphocyte development and humoral responsiveness

SRPK3 regulates alternative pre-mRNA splicing required for B lymphocyte development and humoral responsiveness

Effect of Photobiomodulation on Wound Healing of the Corneal Epithelium through Rho-GTPase

The role of metabolic checkpoint regulators in B cell survival and transformation

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