Identification of the glycosaminoglycan-attachment site of mouse invariant-chain proteoglycan core protein by site-directed mutagenesis.

Miller, Jim; Hatch, Julie A.; Simonis, Simonetta; Cullen, Susan E.

doi:10.1073/pnas.85.5.1359

Cited by 41 publications

(14 citation statements)

References 56 publications

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“…Cardioprotection by MIF is mediated through its intrinsic antioxidant capacity and by signaling through its cognate receptor CD74, a type II transmembrane glycoprotein and the surface form of class II invariant chain 25, 26, 27, 28, 29, 30, 31. In fact, The MIF/CD74/AMPK (adenosine monophosphate kinase) signaling pathway has repeatedly been demonstrated to play a pivotal protective role in acute myocardial ischemia/reperfusion injury 31, 32, 33.…”

Section: Introductionmentioning

confidence: 99%

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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BackgroundAlthough macrophage migration inhibitory factor (MIF) has been demonstrated to mediate cardioprotection in ischemia/reperfusion injury and antagonize fibrotic effects through its receptor, CD74, the function of the soluble CD74 receptor ectodomain (sCD74) and its interaction with circulating MIF have not been explored in cardiac disease.Methods and ResultsCardiac fibroblasts were isolated from hearts of neonatal mice and differentiated into myofibroblasts. Co‐treatment with recombinant MIF and sCD74 induced cell death (P<0.001), which was mediated by receptor‐interacting serine/threonine‐protein kinase (RIP)1/RIP3‐dependent necroptosis (P=0.0376). This effect was specific for cardiac fibroblasts and did not affect cardiomyocytes. Gene expression analyses using microarray and RT‐qPCR technology revealed a 4‐fold upregulation of several interferon‐induced genes upon co‐treatment of myofibroblasts with sCD74 and MIF (Ifi44: P=0.011; Irg1: P=0.022; Clec4e: P=0.011). Furthermore, Western blot analysis confirmed the role of sCD74 as a modulator of MIF signaling by diminishing MIF‐mediated protein kinase B (AKT) activation (P=0.0197) and triggering p38 activation (P=0.0641). We obtained evidence that sCD74 inhibits MIF‐mediated survival pathway through the C‐X‐C chemokine receptor 4/AKT axis, enabling the induction of CD74‐dependent necroptotic processes in cardiac myofibroblasts. Preliminary clinical data revealed a lowered sCD74/MIF ratio in heart failure patients (17.47±10.09 versus 1.413±0.6244).ConclusionsThese findings suggest that treatment of cardiac myofibroblasts with sCD74 and MIF induces necroptosis, offering new insights into the mechanism of myofibroblast depletion during scar maturation. Preliminary clinical data provided first evidence about a clinical relevance of the sCD74/MIF axis in heart failure, suggesting that these proteins may be a promising target to modulate cardiac remodeling and disease progression in heart failure.

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Section: Introductionmentioning

confidence: 99%

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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“…with the invariant chain (34) and that was previously shown to influence Ag processing and presentation (35). Altogether, these observations lead to a scenario in which the 37-57 moiety targets the toxin to HSPG expressed on the surface of splenocytes and, thus, increases its T cell-stimulating capacity.…”

Section: Discussionmentioning

confidence: 76%

Cell Surface Heparan Sulfate Proteoglycans Influence MHC Class II-Restricted Antigen Presentation

Léonetti

Gadzinski

Moine

2010

The Journal of Immunology

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“…This proteoglycan form of Ii is found associated with MHCII at the cell surface [28,29]. In this report, we increased the percentage of Ii modified by CS addition by changing the xylosylation site in Ii to conform more closely to the consensus sequence for xylosyltransferase.…”

Section: Discussionmentioning

confidence: 86%

“…A small amount of total cellular Ii (2-5 %) is modified by the addition of the CS glycosaminoglycan side chain at amino acid position 201 [28,29]. When we compared the CS addition site in Ii with the consensus sequence for xylosylation [30][31][32][33], we found two significant differences that might account for the paucity of Ii-CS ( Figure 1).…”

Section: Resultsmentioning

confidence: 99%

The chondroitin sulfate form of invariant chain trimerizes with conventional invariant chain and these complexes are rapidly transported from thetrans-Golgi network to the cell surface

Arneson

Miller

2007

Biochemical Journal

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Targeting of MHCII-invariant chain complexes from the transGolgi network to endosomes is mediated by two di-leucinebased signals present in the cytosolic domain of invariant chain. Generation of this endosomal targeting signal is also dependent on multimerization of the invariant chain cytosolic domain sequences, mediated through assembly of invariant chain into homotrimers. A small subset of invariant chain is modified by the addition of chondroitin sulfate and is expressed on the cell surface in association with MHCII. In the present study, we have followed the biosynthetic pathway and route of intracellular transport of this proteoglycan form of invariant chain. We found that the efficiency of chondroitin sulfate modification can be increased by altering the invariant chain amino acid sequence around Ser-201 to the xylosylation consensus sequence. Our results also indicate that, following sulfation, the proteoglycan form is transported rapidly from the trans-Golgi network to the cell surface and is degraded following internalization into an endocytic compartment. Invariant chain-chondroitin sulfate is present in invariant chain trimers that also include conventional non-proteoglycan forms of invariant chain. These data indicate that invariant chain-chondroitin sulfate-containing complexes are transported rapidly from the trans-Golgi network to the cell surface in spite of the presence of an intact endosomal localization signal. Furthermore, these results suggest that invariant chainchondroitin sulfate may play an important role in the generation of cell-surface pools of invariant chain that can serve as receptors for CD44 and macrophage migration inhibitory factor.

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Identification of the glycosaminoglycan-attachment site of mouse invariant-chain proteoglycan core protein by site-directed mutagenesis.

Cited by 41 publications

References 56 publications

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Cell Surface Heparan Sulfate Proteoglycans Influence MHC Class II-Restricted Antigen Presentation

The chondroitin sulfate form of invariant chain trimerizes with conventional invariant chain and these complexes are rapidly transported from thetrans-Golgi network to the cell surface

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