Reduced levels of Hspa9 attenuate Stat5 activation in mouse B cells

Krysiak, Kilannin; Tibbitts, Justin; Shao, Jin; Liu, Tuoen; Ndonwi, Matthew; Walter, Matthew J.

doi:10.1016/j.exphem.2014.12.005

Cited by 14 publications

(11 citation statements)

References 58 publications

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“…Furthermore, in EVs associated with C. neoformans (live-BM-EVs and Hk-BM-EVs), higher levels of alarmin proteins, GRIA1, ARFGEF1/2, and HSPA9, were identified as shared components. These proteins are immunity modulators via pathways such as STAT5 ( 31 ). Notably, GRIA1, a regulator in glutamatergic signaling ( 32 ), and HSPA9, a stress-associated protein ( 33 ), were detected only in EVs from infected macrophages, suggesting specific roles in intercellular communication during infection.…”

Section: Discussionmentioning

confidence: 99%

Cryptococcus neoformans-Infected Macrophages Release Proinflammatory Extracellular Vesicles: Insight into Their Components by Multi-omics

Zhang

et al. 2021

mBio

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Cryptococcus neoformans causes deadly mycosis in immunocompromised individuals. Macrophages are key cells fighting against microbes. Extracellular vesicles (EVs) are cell-to-cell communication mediators. The roles of EVs from infected host cells in the interaction with Cryptococcus remain uninvestigated. Here, EVs from viable C. neoformans-infected macrophages reduced fungal burdens but led to shorter survival of infected mice. In vitro, EVs induced naive macrophages to an inflammatory phenotype. Transcriptome analysis showed that EVs from viable C. neoformans-infected macrophages activated immune-related pathways, including p53 in naive human and murine macrophages. Conserved analysis demonstrated that basic cell biological processes, including cell cycle and division, were activated by infection-derived EVs from both murine and human infected macrophages. Combined proteomics, lipidomics, and metabolomics of EVs from infected macrophages showed regulation of pathways such as extracellular matrix (ECM) receptors and phosphatidylcholine. This form of intermacrophage communication could serve to prepare cells at more distant sites of infection to resist C. neoformans infection. IMPORTANCE Cryptococcus neoformans causes cryptococcal meningitis, which is frequent in patients with HIV/AIDS, especially in less-developed countries. The incidence of cryptococcal meningitis is close to 1 million each year globally. Macrophages are key cells that protect the body against microbes, including C. neoformans. Extracellular vesicles are a group of membrane structures that are released from cells such as macrophages that modulate cell activities via the transfer of materials such as proteins, lipids, and RNAs. In this study, we found that Cryptococcus neoformans-infected macrophages produce extracellular vesicles that enhance the inflammatory response in Cryptococcus-infected mice. These Cryptococcus neoformans-infected macrophage vesicles also showed higher fungicidal biological effects on inactivated macrophages. Using omics technology, unique protein and lipid signatures were identified in these extracellular vesicles. Transcriptome analysis showed that these vesicles activated immune-related pathways like p53 in naive macrophages. The understanding of this intermacrophage communication could provide potential targets for the design of therapeutic agents to fight this deadly mycosis.

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Section: Discussionmentioning

confidence: 99%

Cryptococcus neoformans-Infected Macrophages Release Proinflammatory Extracellular Vesicles: Insight into Their Components by Multi-omics

Zhang

et al. 2021

mBio

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“…The level of HSPA9 expression and timing of deletion may be important for these phenotypes, as we have previously reported that constitutive heterozygous deletion of Hspa9 in mice does not result in cytopenias. [ 11 ] This suggests that compensation for a constitutive deletion of Hspa9 may occur during mouse development. HSPA1A, another Hsp70 family member, has been shown to regulate erythropoiesis by preventing active caspase-3 from cleaving GATA1 in the nucleus and inducing apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…[ 9 , 10 ] In addition, complete loss of Hspa9 in mice is early embryonic lethal, suggesting that reducing HSPA9 levels below 50% may be lethal to cells. [ 11 ] Consistent with complete loss of Hspa9 being lethal, HSPA9 has recently been identified as an essential gene in human cells. [ 36 , 37 ] Inherited variants in HSPA9 have also been associated with congenital sideroblastic anemia with data suggesting >50% reduction is required to cause this phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…[ 8 ] Knockdown of Hspa9 in a mouse bone marrow transduction transplantation model showed reduction in hematopoietic stem and progenitor cells [ 9 , 10 ] and heterozygous deletion of Hspa9 in mice alters B-cell lymphopoiesis. [ 11 ] Collectively, these studies revealed important functions of HSPA9 in hematopoiesis, suggesting it may contribute to the increased apoptosis observed in MDS.…”

Section: Introductionmentioning

confidence: 97%

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Knockdown of HSPA9 induces TP53-dependent apoptosis in human hematopoietic progenitor cells

et al. 2017

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Myelodysplastic syndromes (MDS) are the most common adult myeloid blood cancers in the US. Patients have increased apoptosis in their bone marrow cells leading to low peripheral blood counts. The full complement of gene mutations that contribute to increased apoptosis in MDS remains unknown. Up to 25% of MDS patients harbor and acquired interstitial deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes including HSPA9. Knockdown of HSPA9 in primary human CD34+ hematopoietic progenitor cells significantly inhibits growth and increases apoptosis. We show here that HSPA9 knockdown is associated with increased TP53 expression and activity, resulting in increased expression of target genes BAX and p21. HSPA9 protein interacts with TP53 in CD34+ cells and knockdown of HSPA9 increases nuclear TP53 levels, providing a possible mechanism for regulation of TP53 by HSPA9 haploinsufficiency in hematopoietic cells. Concurrent knockdown of TP53 and HSPA9 rescued the increased apoptosis observed in CD34+ cells following knockdown of HSPA9. Reduction of HSPA9 below 50% results in severe inhibition of cell growth, suggesting that del(5q) cells may be preferentially sensitive to further reductions of HSPA9 below 50%, thus providing a genetic vulnerability to del(5q) cells. Treatment of bone marrow cells with MKT-077, an HSPA9 inhibitor, induced apoptosis in a higher percentage of cells from MDS patients with del(5q) compared to non-del(5q) MDS patients and normal donor cells. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to TP53 activation and increased apoptosis observed in del(5q)-associated MDS.

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“…This heat-shock protein is involved in the translocation of proteins from the cytosol into the mitochondrial matrix, in the folding of such imported proteins and in the response to oxidative stress [ 44 , 45 ]. Deletion of the HSPA9 locus (5q31.1) is a frequent finding in myeloid malignancies [ 46 ]. In other settings, HSPA9 exhibits oncogenic properties, making it a potential therapeutic target for cancer.…”

Section: Discussionmentioning

confidence: 99%

Multi-chaperone function modulation and association with cytoskeletal proteins are key features of the function of AIP in the pituitary gland

et al. 2018

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Despite the well-recognized role of loss-of-function mutations of the aryl hydrocarbon receptor interacting protein gene (AIP) predisposing to pituitary adenomas, the pituitary-specific function of this tumor suppressor remains an enigma. To determine the repertoire of interacting partners for the AIP protein in somatotroph cells, wild-type and variant AIP proteins were used for pull-down/quantitative mass spectrometry experiments against lysates of rat somatotropinoma-derived cells; relevant findings were validated by co-immunoprecipitation and co-localization. Global gene expression was studied in AIP mutation positive and negative pituitary adenomas via RNA microarrays. Direct interaction with AIP was confirmed for three known and six novel partner proteins. Novel interactions with HSPA5 and HSPA9, together with known interactions with HSP90AA1, HSP90AB1 and HSPA8, indicate that the function/stability of multiple chaperone client proteins could be perturbed by a deficient AIP co-chaperone function. Interactions with TUBB, TUBB2A, NME1 and SOD1 were also identified. The AIP variants p.R304* and p.R304Q showed impaired interactions with HSPA8, HSP90AB1, NME1 and SOD1; p.R304* also displayed reduced binding to TUBB and TUBB2A, and AIP-mutated tumors showed reduced TUBB2A expression. Our findings suggest that cytoskeletal organization, cell motility/adhesion, as well as oxidative stress responses, are functions that are likely to be involved in the tumor suppressor activity of AIP.

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Reduced levels of Hspa9 attenuate Stat5 activation in mouse B cells

Cited by 14 publications

References 58 publications

Cryptococcus neoformans-Infected Macrophages Release Proinflammatory Extracellular Vesicles: Insight into Their Components by Multi-omics

Cryptococcus neoformans-Infected Macrophages Release Proinflammatory Extracellular Vesicles: Insight into Their Components by Multi-omics

Knockdown of HSPA9 induces TP53-dependent apoptosis in human hematopoietic progenitor cells

Multi-chaperone function modulation and association with cytoskeletal proteins are key features of the function of AIP in the pituitary gland

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