YB-1 Is an Early and Central Mediator of Bacterial and Sterile Inflammation In Vivo

Hanssen, Lydia; Alidousty, Christina; Djudjaj, Sonja; Frye, Björn C.; Rauen, Thomas; Boor, Peter; Mertens, Peter R.; Roeyen, Claudia R. van; Tacke, Frank; Heymann, Felix; Tittel, André P.; Koch, Alexander; Floege, Jürgen; Ostendorf, Tammo; Raffetseder, Ute

doi:10.4049/jimmunol.1300416

Cited by 61 publications

(61 citation statements)

References 39 publications

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“…32,33 Flow-cytometric analyses of the primary cultures showed that PECs, podocytes, and mesangial cells expressed CD74, whereas only PECs and mesangial cells coexpressed CD44 ( Figure 3A), confirming our in vivo immunohistochemic data. None of the cell types showed detectable CXCR2 expression and only faint CXCR4 levels.…”

Section: Mif Receptor Expression In Glomerular Cells In Vitrosupporting

confidence: 79%

Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74

Djudjaj¹,

Lue

Rong³

et al. 2015

JASN

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Pathologic proliferation of mesangial and parietal epithelial cells (PECs) is a hallmark of various glomerulonephritides. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that mediates inflammation by engagement of a receptor complex involving the components CD74, CD44, CXCR2, and CXCR4. The proliferative effects of MIF may involve CD74 together with the coreceptor and PEC activation marker CD44. Herein, we analyzed the effects of local glomerular MIF/CD74/CD44 signaling in proliferative glomerulonephritides. MIF, CD74, and CD44 were upregulated in the glomeruli of patients and mice with proliferative glomerulonephritides. During disease, CD74 and CD44 were expressed de novo in PECs and colocalized in both PECs and mesangial cells. Stress stimuli induced MIF secretion from glomerular cells in vitro and in vivo, in particular from podocytes, and MIF stimulation induced proliferation of PECs and mesangial cells via CD74. In murine crescentic GN, Mif-deficient mice were almost completely protected from glomerular injury, the development of cellular crescents, and the activation and proliferation of PECs and mesangial cells, whereas wild-type mice were not. Bone marrow reconstitution studies showed that deficiency of both nonmyeloid and bone marrow-derived Mif reduced glomerular cell proliferation and injury. In contrast to wild-type mice, Cd74-deficient mice also were protected from glomerular injury and ensuing activation and proliferation of PECs and mesangial cells. Our data suggest a novel molecular mechanism and glomerular cell crosstalk by which local upregulation of MIF and its receptor complex CD74/CD44 mediate glomerular injury and pathologic proliferation in GN.

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Section: Mif Receptor Expression In Glomerular Cells In Vitrosupporting

confidence: 79%

Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74

Djudjaj¹,

Lue

Rong³

et al. 2015

JASN

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“…There is increasing evidence that YB-1 has an important regulatory role in various inflammatory diseases, such as allergic asthma (31), transplant rejection (17), atherosclerosis (18), sepsis, and sterile inflammation (16). In previous studies, our group identified YB-1 as a cell-type-specific regulator of the chemokine CCL5 (17,18), a key chemotactic factor for immune cell infiltration.…”

Section: Discussionmentioning

confidence: 95%

“…Co-immunoprecipitation of CN Associated with YB-1-Prior to immunoprecipitation, polyclonal anti-calcineurin antibody (Cell Signaling) and nonspecific rabbit IgG (Santa Cruz Biotechnology) as negative control were covalently linked to protein A-Sepharose beads (50% suspension; Invitrogen), as described before (16). A total of 40 l of protein A-Sepharose coupled with either polyclonal CN antibody or nonspecific IgG was incubated with 200 g of total cell extracts or cytoplasmic (200 g) and nuclear (100 g) protein extracts from HEK293T cells, respectively, for 90 min at 4°C in immunoprecipitation buffer (20 mM HEPES, 100 mM potassium chloride, 5 mM magnesium acetate, 1 mM DTT, 0.025% Triton X-100, and protease inhibitors).…”

Section: Methodsmentioning

confidence: 99%

“…The Ser/Thr phosphatase PP2C␥ is involved in spliceosome assembly and has been shown to interact with YB-1 (15); however, a subsequent change in the phosphorylation state of YB-1 has not been investigated so far. In vivo and ex vivo data demonstrate that YB-1 is post-translationally phosphorylated at amino acid position 102 (serine 102 (Ser-102)) at the onset of lipopolysaccharide (LPS)-triggered inflammation (16). However, this modification is no longer detectable during the late phase of inflammation, pointing to a reversible phosphorylation of YB-1 (16).…”

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confidence: 99%

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Calcineurin-mediated YB-1 Dephosphorylation Regulates CCL5 Expression during Monocyte Differentiation

Alidousty

Rauen

Hanssen

et al. 2014

Journal of Biological Chemistry

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Background: Transcription factor YB-1 constitutes a key regulator in immune cell homeostasis. It has been demonstrated to be involved in monocyte/macrophage differentiation. However, the underlying mechanisms are poorly understood. Results: Protein phosphatase calcineurin (CN) regulates YB-1 activities on the CCL5 promoter during macrophage differentiation. Conclusion: Dephosphorylation of YB-1 by CN is crucial to counteract the overwhelming pro-inflammatory propensities of YB-1. Significance: Overshooting inflammation may be counteracted by dephosphorylation of YB-1.

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“…[16][17][18][19] YB-1 is a highly conserved protein involved in the regulation of inflammatory processes, including sterile inflammation in renal diseases. 19 YB-1 conveys multiple functions through its interaction with DNA, mRNA, and proteins.…”

mentioning

confidence: 99%

Activated Protein C Ameliorates Renal Ischemia-Reperfusion Injury by Restricting Y-Box Binding Protein-1 Ubiquitination

Wang¹,

Wang

Shahzad

et al. 2015

Journal of the American Society of Nephrology

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Ischemia-reperfusion injury (IRI) is the leading cause of ARF. A pathophysiologic role of the coagulation system in renal IRI has been established, but the functional relevance of thrombomodulin (TM)-dependent activated protein C (aPC) generation and the intracellular targets of aPC remain undefined. Here, we investigated the role of TM-dependent aPC generation and therapeutic aPC application in a murine renal IRI model and in an in vitro hypoxia and reoxygenation (HR) model using proximal tubular cells. In renal IRI, endogenous aPC levels were reduced. Genetic or therapeutic reconstitution of aPC efficiently ameliorated renal IRI independently of its anticoagulant properties. In tubular cells, cytoprotective aPC signaling was mediated through protease activated receptor-1-and endothelial protein C receptor-dependent regulation of the cold-shock protein Y-box binding protein-1 (YB-1). The mature 50 kD form of YB-1 was required for the nephro-and cytoprotective effects of aPC in vivo and in vitro, respectively. Reduction of mature YB-1 and K48-linked ubiquitination of YB-1 was prevented by aPC after renal IRI or tubular HR injury. aPC preserved the interaction of YB-1 with the deubiquitinating enzyme otubain-1 and maintained expression of otubain-1, which was required to reduce K48-linked YB-1 ubiquitination and to stabilize the 50 kD form of YB-1 after renal IRI and tubular HR injury. These data link the cyto-and nephroprotective effects of aPC with the ubiquitin-proteasome system and identify YB-1 as a novel intracellular target of aPC. These insights may provide new impetus for translational efforts aiming to restrict renal IRI.

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YB-1 Is an Early and Central Mediator of Bacterial and Sterile Inflammation In Vivo

Cited by 61 publications

References 39 publications

Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74

Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74

Calcineurin-mediated YB-1 Dephosphorylation Regulates CCL5 Expression during Monocyte Differentiation

Activated Protein C Ameliorates Renal Ischemia-Reperfusion Injury by Restricting Y-Box Binding Protein-1 Ubiquitination

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