CD74 is a novel transcription regulator

Gil-Yarom, Naama; Radomir, Lihi; Sever, Lital; Kramer, Matthias P.; Lewinsky, Hadas; Bornstein, Chamutal; Blecher‐Gonen, Ronnie; Barnett-Itzhaki, Zohar; Mirkin, Vita; Friedlander, Gilgi; Shvidel, Lev; Herishanu, Yair; Lolis, Elias; Becker-Herman, Shirly; Amit, Ido; Shachar, Idit

doi:10.1073/pnas.1612195114

Cited by 118 publications

(96 citation statements)

References 48 publications

(58 reference statements)

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“…Surprisingly, no upregulation of NFkB-regulated genes has been detected in this study, an effect well established for ICD in the 293T cell line as well as in primary B-cells [17,24,29,104]. The latter observations have been recently confirmed and largely extended in the context of the B-cell malignancy chronic lymphocytic leukemia [106]. The authors analyzed the chromatin binding sites of ICD and its effects on transcription by a low bias approach involving chromatin immunoprecipitation sequencing and RNA sequencing.…”

Section: Mif-induced Signaling From Invariant Chain Complexessupporting

confidence: 79%

“…Although a requirement for the NFκB p65/RelA homodimer for B-cell maturation was demonstrated early-on [17], only very recently an interaction between ICD and the transcription factors Runx1,3 and RelA, but not RelB, has been shown by pulldown from human B lymphoma cells [106]. The authors were also able to detect ICD-RelA complexes in fractions derived from the cytosol and the nucleus, suggesting that ICD bound to Rel A in the cytoplasm prior to the import of the complex into the nucleus.…”

Section: Mif-induced Signaling From Invariant Chain Complexesmentioning

confidence: 99%

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Invariant Chain Complexes and Clusters as Platforms for MIF Signaling

Lindner

2017

Cells

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Invariant chain (Ii/CD74) has been identified as a surface receptor for migration inhibitory factor (MIF). Most cells that express Ii also synthesize major histocompatibility complex class II (MHC II) molecules, which depend on Ii as a chaperone and a targeting factor. The assembly of nonameric complexes consisting of one Ii trimer and three MHC II molecules (each of which is a heterodimer) has been regarded as a prerequisite for efficient delivery to the cell surface. Due to rapid endocytosis, however, only low levels of Ii-MHC II complexes are displayed on the cell surface of professional antigen presenting cells and very little free Ii trimers. The association of Ii and MHC II has been reported to block the interaction with MIF, thus questioning the role of surface Ii as a receptor for MIF on MHC II-expressing cells. Recent work offers a potential solution to this conundrum: Many Ii-complexes at the cell surface appear to be under-saturated with MHC II, leaving unoccupied Ii subunits as potential binding sites for MIF. Some of this work also sheds light on novel aspects of signal transduction by Ii-bound MIF in B-lymphocytes: membrane raft association of Ii-MHC II complexes enables MIF to target Ii-MHC II to antigen-clustered B-cell-receptors (BCR) and to foster BCR-driven signaling and intracellular trafficking.

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Section: Mif-induced Signaling From Invariant Chain Complexessupporting

confidence: 79%

Section: Mif-induced Signaling From Invariant Chain Complexesmentioning

confidence: 99%

Invariant Chain Complexes and Clusters as Platforms for MIF Signaling

Lindner

2017

Cells

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“…Data represent the mean with standard errors from at least four mice for each genotype. The EMBO Journal TAMs require ZEB1 for their tumor-promoting roles Marlies Cortés et al respectively; Aldh1a1 and Kit, two cancer stem cell markers whose expression is associated with tumor progression in ovarian and other cancers (Chau et al, 2011;Silva et al, 2011); Mdr1 (Abcb1), an efflux drug transporter associated with chemotherapy resistance (Gottesman et al, 2002); and Cd74, which is expressed by both F4/80 low macrophages and ovarian cancer cells and that activates CCL2 transcription and promotes tumor progression (Wilkinson et al, 2015;Gil-Yarom et al, 2017). Interestingly, Zeb1 was higher in ID8 cells isolated from wild-type mice than in those from Zeb1 (+/À) mice ( Fig 3E).…”

Section: Tams Require Expression Of Full Levels Of Zeb1 To Promote Tumentioning

confidence: 99%

Tumor‐associated macrophages (TAMs) depend on ZEB1 for their cancer‐promoting roles

et al. 2017

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Accumulation of tumor-associated macrophages (TAMs) associates with malignant progression in cancer. However, the mechanisms that drive the pro-tumor functions of TAMs are not fully understood. ZEB1 is best known for driving an epithelial-to-mesenchymal transition (EMT) in cancer cells to promote tumor progression. However, a role for ZEB1 in macrophages and TAMs has not been studied. Here we describe that TAMs require ZEB1 for their tumor-promoting and chemotherapy resistance functions in a mouse model of ovarian cancer. Only TAMs that expressed full levels of accelerated tumor growth. Mechanistically, ZEB1 expression in TAMs induced their polarization toward an F4/80 pro-tumor phenotype, including direct activation of In turn, expression of ZEB1 by TAMs induced and a mesenchymal/stem-like phenotype in cancer cells. In human ovarian carcinomas, TAM infiltration and CCR2 expression correlated with ZEB1 in tumor cells, where along with CCL2 and CD74 determined poorer prognosis. Importantly, ZEB1 in TAMs was a factor of poorer survival in human ovarian carcinomas. These data establish ZEB1 as a key factor in the tumor microenvironment and for maintaining TAMs' tumor-promoting functions.

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“…Ectodomain shedding represents an important posttranslational modification event that downregulates cell‐surface expression of various receptors and liberates biologically active fragments that often exhibit a function that is distinct from that of the membrane‐bound receptor form 38. Although the effects of the intracellular domain of CD74, released following regulated intracellular proteolysis, have been extensively studied,39, 40, 41 we are only beginning to understand the functions of the CD74 ectodomain 37, 39, 42, 43, 44…”

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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CD74 is a novel transcription regulator

Cited by 118 publications

References 48 publications

Invariant Chain Complexes and Clusters as Platforms for MIF Signaling

Invariant Chain Complexes and Clusters as Platforms for MIF Signaling

Tumor‐associated macrophages (TAMs) depend on ZEB1 for their cancer‐promoting roles

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

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