T cell development and the physiological role of <i>O</i>‐GlcNAc

Abramowitz, Lara K.; Hanover, John A.

doi:10.1002/1873-3468.13159

Cited by 19 publications

(41 citation statements)

References 46 publications

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“…7 ). Homeostasis of O - GlcNAc through activities of OGT and OGA has been previously implicated in normal hematopoietic development 96 , 97 , in differentiation arrest of AML and Jurkat T‑cells 98 as well as in other cancers 99 . However, our study is the first to report that this modification is also essential for the survival of MLL-r B-ALL cells.…”

Section: Discussionmentioning

confidence: 99%

Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia

Oliveira¹,

Zhang²,

Joo³

et al. 2021

Theranostics

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B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with mixed-lineage leukemia gene rearrangement (MLL-r) is a poor-prognosis subtype for which additional therapeutic targets are urgently needed. Currently no multi- omics data set for primary MLL r patient cells exists that integrates transcriptomics, proteomics and glycomics to gain an inclusive picture of theranostic targets. Methods: We have integrated transcriptomics, proteomics and glycomics to i) obtain the first inclusive picture of primary patient BCP-ALL cells and identify molecular signatures that distinguish leukemic from normal precursor B-cells and ii) better understand the benefits and limitations of the applied technologies to deliver deep molecular sequence data across major cellular biopolymers. Results: MLL-r cells feature an extensive remodeling of their glycocalyx, with increased levels of Core 2-type O-glycans and complex N-glycans as well as significant changes in sialylation and fucosylation. Notably, glycosaminoglycan remodeling from chondroitin sulfate to heparan sulfate was observed. A survival screen, to determine if glycan remodeling enzymes are redundant, identified MGAT1 and NGLY1, essential components of the N-glycosylation/degradation pathway, as highly relevant within this in vitro screening. OGT and OGA, unique enzymes that regulate intracellular O-GlcNAcylation, were also indispensable. Transcriptomics and proteomics further identified Fes and GALNT7-mediated glycosylation as possible therapeutic targets. While there is overall good correlation between transcriptomics and proteomics data, we demonstrate that a systematic combined multi- omics approach delivers important diagnostic information that is missed when applying a single omics technology. Conclusions: Apart from confirming well-known MLL-r BCP-ALL glycoprotein markers, our integrated multi- omics workflow discovered previously unidentified diagnostic/therapeutic protein targets.

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Section: Discussionmentioning

confidence: 99%

Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia

Oliveira¹,

Zhang²,

Joo³

et al. 2021

Theranostics

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“…various cellular processes, such as cell growth, mobility, metabolism, and development, by regulating protein stability, localization, activity, and protein-protein interactions (30)(31)(32)(33)(34)(35)(36). In particular, it is well known that O-GlcNAcylation regulates phosphorylationmediated signaling pathways through interplay with phosphorylation (37,38).…”

Section: Significancementioning

confidence: 99%

O -GlcNAcylation on LATS2 disrupts the Hippo pathway by inhibiting its activity

Kim

Kang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The Hippo pathway controls organ size and tissue homeostasis by regulating cell proliferation and apoptosis. The LATS-mediated negative feedback loop prevents excessive activation of the effectors YAP/TAZ, maintaining homeostasis of the Hippo pathway. YAP and TAZ are hyperactivated in various cancer cells which lead to tumor growth. Aberrantly increased O-GlcNAcylation has recently emerged as a cause of hyperactivation of YAP in cancer cells. However, the mechanism, which induces hyperactivation of TAZ and blocks LATS-mediated negative feedback, remains to be elucidated in cancer cells. This study found that in breast cancer cells, abnormally increased O-GlcNAcylation hyperactivates YAP/TAZ and inhibits LATS2, a direct negative regulator of YAP/TAZ. LATS2 is one of the newly identified O-GlcNAcylated components in the MST-LATS kinase cascade. Here, we found that O-GlcNAcylation at LATS2 Thr436 interrupted its interaction with the MOB1 adaptor protein, which connects MST to LATS2, leading to activation of YAP/TAZ by suppressing LATS2 kinase activity. LATS2 is a core component in the LATS-mediated negative feedback loop. Thus, this study suggests that LATS2 O-GlcNAcylation is deeply involved in tumor growth by playing a critical role in dysregulation of the Hippo pathway in cancer cells.

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“…Thus, PHB expression and functions may be altered in obesity and obesity-related abnormalities, such as insulin resistance and low-grade chronic inflammation. Furthermore, accumulating evidence suggests that PHB and OGT play an important role in different immune cell types [27–32, 97] and OGT is highly expressed in lymphocytes and lymphoid tissues [32, 98, 99]. Thus, PHB and OGT may be a part of sex steroid signaling in metabolic tissues and in the regulation of insulin signaling in a sex-specific manner.…”

Section: Does Alternate O-glcnacylation and Phosphorylation Of Phb Atmentioning

confidence: 99%

Prohibitin: a prime candidate for a pleiotropic effector that mediates sex differences in obesity, insulin resistance, and metabolic dysregulation

Bassi

Mishra

2019

Biol Sex Differ

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Adipocytes and macrophages, the two major constituents of adipose tissue, exhibit sex differences and work in synergy in adipose tissue physiology and pathophysiology, including obesity-linked insulin resistance and metabolic dysregulation. Sex steroid hormones play a major role in sex differences in adipose tissue biology. However, our knowledge of the molecules that mediate these effects in adipose tissue remains limited. Consequently, it remains unclear whether these effector molecules in different adipose and immune cell types are distinct or if there are also pleiotropic effectors. Recently, a protein named prohibitin (PHB) with cell compartment-and tissue-specific functions has been found to play a role in sex differences in adipose and immune functions. Transgenic (Tg) mouse models overexpressing PHB (PHB-Tg) and a phospho-mutant PHB (mPHB-Tg) from the fatty acid binding protein-4 (Fabp-4) gene promoter display sex-neutral obesity; however, obesity-related insulin resistance and metabolic dysregulation are male-specific. Intriguingly, with aging, the male PHB-Tg mice developed hepatic steatosis and subsequently liver tumors whereas the male mPHB-Tg mice developed lymph node tumors and splenomegaly. Unlike the male transgenic mice, the female PHB-Tg and mPHB-Tg mice remain protected from obesity-related metabolic dysregulation and tumor development. In conclusion, the sex-dimorphic metabolic and immune phenotypes of PHB-Tg and mPHB-Tg mice have revealed PHB as a pleiotropic effector of sex differences in adipose and immune functions. In this mini-review, we will discuss the pleiotropic attributes of PHB and potential mechanisms that may have contributed to the sex-dimorphic metabolic phenotypes in PHB-Tg and mPHB-Tg mice, which warrant future research. We propose that PHB is a prime candidate for a pleiotropic mediator of sex differences in adipose and immune functions in both physiology and pathophysiology, including obesity, insulin resistance, and metabolic dysregulation.

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T cell development and the physiological role of O‐GlcNAc

Cited by 19 publications

References 46 publications

Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia

Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia

O -GlcNAcylation on LATS2 disrupts the Hippo pathway by inhibiting its activity

Prohibitin: a prime candidate for a pleiotropic effector that mediates sex differences in obesity, insulin resistance, and metabolic dysregulation

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