The mTOR-Bach2 Cascade Controls Cell Cycle and Class Switch Recombination during B Cell Differentiation

Tamahara, Toru; Ochiai, Kyoko; Muto, Akihiko; Kato, Yukinari; Sax, Nicolas; Matsumoto, Mitsuyo; Koseki, Takeyoshi; Igarashi, Kazuhiko

doi:10.1128/mcb.00418-17

Cited by 32 publications

(25 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PI3K is likely to participate in this process. Prolonged PI3K activity decreases BACH2 through at least two different mechanisms: (a) at the protein level, through AKT‐mTORC1–mediated phosphorylation of BACH2, leading to cytoplasmic localization and degradation; (b) at the mRNA level, through inhibition of FOXO1 which promotes Bach2 transcription . BACH2 also blocks Prdm1 expression and therefore PC differentiation (Figures and ).…”

Section: Pi3k In Plasma Cell and Memory B‐cell Formationmentioning

confidence: 97%

T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

Preite

Gómez-Rodríguez

Cannons

et al. 2019

Immunological Reviews

View full text Add to dashboard Cite

Phosphatidylinositol 3 kinases (PI3K) are a family of lipid kinases that are activated by a variety of cell-surface receptors, and regulate a wide range of downstream readouts affecting cellular metabolism, growth, survival, differentiation, adhesion, and migration. The importance of these lipid kinases in lymphocyte signaling has recently been highlighted by genetic analyses, including the recognition that both activating and inactivating mutations of the catalytic subunit of PI3Kδ, p110δ, lead to human primary immunodeficiencies. In this article, we discuss how studies on the human genetic disorder "Activated PI3K-delta syndrome" and mouse models of this disease (Pik3cd E1020K/+ mice) have provided fundamental insight into pathways regulated by PI3Kδ in T and B cells and their contribution to lymphocyte function and disease, including responses to commensal bacteria and the development of autoimmunity and tumors. We highlight critical roles of PI3Kδ in T follicular helper cells and the orchestration of the germinal center reaction, as well as in CD8 + T-cell function. We further present data demonstrating the ability of the AKT-resistant FOXO1 AAA mutant to rescue IgG1 class switching defects in Pik3cd E1020K/+ B cells, as well as data supporting a role for PI3Kδ in promoting multiple T-helper effector cell lineages. K E Y W O R D S APDS/PASLI, autoimmunity, immunodeficiency, phosphatidylinositol 3 kinase, T and B lymphocytes | 155 PREITE ET al. | AC TIVATED PI3K-DELTA SYNDROMEIn 2013-2014, three studies described immunodeficient patients with heterozygous gain-of-function autosomal-dominant mutations in PIK3CD, the gene encoding the catalytic subunit of PI3K p110δ. [3][4][5] At least 11 mutations have now been identified by whole exome sequencing, with the E1021K mutant being most prevalent. 2,6 Based on similar mutations in PI3Kα found in cancers and overgrowth syndromes, p110δ mutations were predicted to activate p110δ. 4,7 Indeed, increased PI3K activity and downstream readouts including increased PIP 3 levels, pAKT and pS6, have been observed in cells from these patients. 3,4 This novel PID has been named "Activated PI3K-delta syndrome" (APDS) or "p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency" (PASLI), hereafter referred to as APDS. Activated PI3K-delta syndrome is a combined immunodeficiency syndrome characterized by altered T-and B-cell development and responses. APDS is associated with frequent respiratory infections, progressive blood lymphopenia, mucosal lymphoid nodules, defective antibody responses, and lymphoma development. 2 Patients exhibit a paucity of naïve peripheral blood T cells with a large fraction of T cells displaying activation markers. In contrast, B-cell development is partially blocked, with increased transitional and few circulating memory B cells. 4,8,9 Recurrent respiratory infections are the most common feature of APDS. However, Epstein-Barr virus (EBV) and/ or cytomegalovirus (CMV) viremia occurs in a substantial fraction of patients, ...

show abstract

Section: Pi3k In Plasma Cell and Memory B‐cell Formationmentioning

confidence: 97%

T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

Preite

Gómez-Rodríguez

Cannons

et al. 2019

Immunological Reviews

View full text Add to dashboard Cite

show abstract

“…In the absence of Bach2, AP-1/IRF4 complex binding is increased, leading to enhanced transcriptional activity in response to TCR signals. Interestingly, the TCR-induced kinase AKT has been identified to inactivate Bach2 by mediating its phosphorylation at Serine-535 [49][50][51] . This provides a feedback mechanism by which the magnitude of the transcriptional response to TCR signals may be further modulated by Bach2.…”

Section: Bach2 Is Required For Of Treg Cell Expansion and Maintenancementioning

confidence: 99%

Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis

et al. 2020

View full text Add to dashboard Cite

Differentiation and homeostasis of Foxp3 + regulatory T (Treg) cells are strictly controlled by T-cell receptor (TCR) signals; however, molecular mechanisms that govern these processes are incompletely understood. Here we show that Bach2 is an important regulator of Treg cell differentiation and homeostasis downstream of TCR signaling. Bach2 prevents premature differentiation of fully suppressive effector Treg (eTreg) cells, limits IL-10 production and is required for the development of peripherally induced Treg (pTreg) cells in the gastrointestinal tract. Bach2 attenuates TCR signaling-induced IRF4-dependent Treg cell differentiation. Deletion of IRF4 promotes inducible Treg cell differentiation and rescues pTreg cell differentiation in the absence of Bach2. In turn, loss of Bach2 normalizes eTreg cell differentiation of IRF4-deficient Treg cells. Mechanistically, Bach2 counteracts the DNA-binding activity of IRF4 and limits chromatin accessibility, thereby attenuating IRF4-dependent transcription. Thus, Bach2 balances TCR signaling induced transcriptional activity of IRF4 to maintain homeostasis of thymically-derived and peripherally-derived Treg cells.

show abstract

“…4) (Dowling et al, 2010;Fingar et al, 2004). A recent study has also demonstrated that mTOR regulates B-cell proliferation by controlling the transcription and translation of the BACH2 transcription factor, which targets cyclin D3 to initiate the cell cycle (Tamahara et al, 2017). In plants, TOR is highly expressed in rapidly growing tissues such as the embryo, shoot meristem, root meristem and lateral root primordia, implicating the involvement of TOR signaling in cell proliferation (Menand et al, 2002).…”

Section: Downstream Targets Of Torc1mentioning

confidence: 99%

TOR signaling in plants: conservation and innovation

2018

View full text Add to dashboard Cite

Target of rapamycin (TOR) is an evolutionarily conserved protein kinase that plays a central role in both plants and animals, despite their distinct developmental programs and survival strategies. Indeed, TOR integrates nutrient, energy, hormone, growth factor and environmental inputs to control proliferation, growth and metabolism in diverse multicellular organisms. Here, we compare the molecular composition, upstream regulators and downstream signaling relays of TOR complexes in plants and animals. We also explore and discuss the pivotal functions of TOR signaling in basic cellular processes, such as translation, cell division and stem/progenitor cell regulation during plant development.

show abstract

The mTOR-Bach2 Cascade Controls Cell Cycle and Class Switch Recombination during B Cell Differentiation

Cited by 32 publications

References 30 publications

T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis

TOR signaling in plants: conservation and innovation

Contact Info

Product

Resources

About