The late endosomal adaptor molecule p14 (LAMTOR2) represents a novel regulator of Langerhans cell homeostasis

Sparber, Florian; Scheffler, Julia M.; Amberg, Nicole; Tripp, Christoph H.; Heib, Valeska; Hermann, Michael; Zahner, Sonja; Clausen, Björn E.; Reizis, Boris; Huber, Lukas A.; Stoitzner, Patrizia; Romani, Nikolaus

doi:10.1182/blood-2013-08-518555

Cited by 50 publications

(66 citation statements)

References 41 publications

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“…In order to assess whether endocytosis and/or microautophagy was disrupted, we examined YS layer-specific expression of several genes related to endocytosis or autophagy including LC3, Tfeb, Lamtor2 and Snx2 (Kabeya et al, 2000; Griffin et al, 2005; Sardiello et al, 2009; Schwarz et al, 2002; Settembre et al, 2011; Sparber et al, 2013; Teis et al, 2006). As expected we found that the expression of these genes was largely restricted to the VE layer ( Figure 6A ).…”

Section: Resultsmentioning

confidence: 99%

Loss of PiT-1 results in abnormal endocytosis in the yolk sac visceral endoderm

Wallingford

Giachelli

2014

Mechanisms of Development

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PiT-1 protein is a transmembrane sodium-dependent phosphate (Pi) transporter. PiT-1 knock out (KO) embryos die from largely unknown causes by embryonic day (E) 12.5. We tested the hypothesis that PiT-1 is required for endocytosis in the embryonic yolk sac (YS) visceral endoderm (VE). Here we present data supporting that PiT-1 KO results in a YS remodeling defect and decreased endocytosis in the YS VE. The remodeling defect is not due to an upstream cardiomyocyte requirement for PiT-1, as SM22αCre-specific KO of PiT-1 in the developing heart and the YS mesodermal layer (ME) does not recapitulate the PiT-1 global KO phenotype. Furthermore, we find that high levels of PiT-1 protein localize to the YS VE apical membrane. Together these data support that PiT-1 is likely required in YS VE. During normal development maternal immunoglobulin (IgG) is endocytosed into YS VE and accumulates in the apical side of the VE in a specialized lysosome termed the apical vacuole (AV). We have identified a reduction in PiT-1 KO VE cell height and a striking loss of IgG accumulation in the PiT-1 KO VE. The endocytosis genes Tfeb, Lamtor2 and Snx2 are increased at the RNA level. Lysotracker Red staining reveals a loss of distinct AVs, and yolk sacs incubated ex vivo with phRODO Green Dextran for Endocytosis demonstrate a functional loss of endocytosis. As yolk sac endocytosis is controlled in part by microautophagy, but expression of LC3 had not been examined, we investigated LC3 expression during yolk sac development and found stage-specific LC3 RNA expression that is predominantly from the YS VE layer at E9.5. Normalized LC3-II protein levels are decreased in the PiT-1 KO YS, supporting a requirement for PiT-1 in autophagy in the YS. Therefore, we propose the novel idea that PiT-1 is central to the regulation of endocytosis and autophagy in the YS VE.

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Section: Resultsmentioning

confidence: 99%

Loss of PiT-1 results in abnormal endocytosis in the yolk sac visceral endoderm

Wallingford

Giachelli

2014

Mechanisms of Development

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“…In contrast, we also demonstrated the marked reduction of LCs in the epidermis of Sirpa DDC mice. Given that CD11c-Cre recombinase directs selective ablation of SIRPa in the epidermal I-A + LCs (Sparber et al 2014) but not in monocytes or macrophages, the present result indicates that SIRPa is likely important for selfrenewal of LCs in the epidermis of skin after arising from their progenitor cells. We also found that the frequency of mDCs was markedly reduced in the pLNs of Sirpa DDC .…”

Section: Cd8amentioning

confidence: 88%

“…Given that expression of Cre recombinase under control of the CD11c-promoter is specific for I-A + LCs in the epidermis (Sparber et al 2014), the number of I-A + cells, which represent LCs (Iwamura et al 2011), was markedly reduced in the epidermal sheets prepared from the ears of Sirpa -/-mice, as well as of Sirpa DDC mice, compared to those of the control mice (Fig. 4).…”

Section: Resultsmentioning

confidence: 99%

Dendritic cell SIRPα regulates homeostasis of dendritic cells in lymphoid organs

et al. 2015

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Signal regulatory protein a (SIRPa), an immunoglobulin superfamily protein that is expressed predominantly in myeloid lineage cells such as dendritic cells (DCs) or macrophages, mediates cell-cell signaling. In the immune system, SIRPa is thought to be important for homeostasis of DCs, but it remains unclear whether SIRPa intrinsic to DCs is indeed indispensable for such functional role. Thus, we here generated the mice, in which SIRPa was specifically ablated in CD11c + DCs (Sirpa DDC ). Sirpa DDC mice manifested a marked reduction of CD4 + CD8a -conventional DCs (cDCs) in the secondary lymphoid organs, as well as of Langerhans cells in the epidermis. Such reduction of cDCs in Sirpa DDC mice was comparable to that apparent with the mice, in which SIRPa was systemically ablated. Expression of SIRPa in DCs was well correlated with that of either endothelial cell-selective adhesion molecule (ESAM) or Epstein-Barr virus-induced molecule 2 (EBI2), both of which were also implicated in the regulation of DC homeostasis. Indeed, ESAM + or EBI2 + cDCs were markedly reduced in the spleen of Sirpa DDC mice. Thus, our results suggest that SIRPa intrinsic to CD11c + DCs is essential for homeostasis of cDCs in the secondary lymphoid organs and skin.

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“…Overall, Raptor ablation in LCs increases their migration and leads to loss of these sentinel DCs in the skin [43]. Further, deletion of the adaptor molecule p14, which is part of the upstream ‘Ragulator’ complex involved in the activation of mTORC1, in DCs ablates the epidermal LC population early after birth due to impaired proliferation and increased apoptosis [48]. …”

Section: Migration Of Dcsmentioning

confidence: 99%

Genetic dissection of dendritic cell homeostasis and function: lessons from cell type-specific gene ablation

Karmaus

Chi

2013

Cell. Mol. Life Sci.

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Dendritic cells (DCs) are a heterogeneous cell population of great importance in the immune system. The emergence of new genetic technology utilizing the CD11c promoter and Cre recombinase has facilitated the dissection of functional significance and molecular regulation of DCs in immune responses and homeostasis in vivo. For the first time, this strategy allows observation of the effects of DC-specific gene deletion on immune system function in an intact organism. In this review, we present the latest findings from studies using the Cre recombinase system for cell type–specific deletion of key molecules that mediate DC homeostasis and function. Our focus is on the molecular pathways that orchestrate DC life span, migration, antigen presentation, pattern recognition, and cytokine production and signaling.

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The late endosomal adaptor molecule p14 (LAMTOR2) represents a novel regulator of Langerhans cell homeostasis

Abstract: Key Points DC-specific ablation of p14 leads to the disruption of the LC network in situ by inducing apoptosis and proliferation deficiency in LCs. p14 deficiency affects ERK/mTOR signaling in DCs and results in transient recruitment of circulation-derived short-term LCs to the skin.

Cited by 50 publications

References 41 publications

Loss of PiT-1 results in abnormal endocytosis in the yolk sac visceral endoderm

Loss of PiT-1 results in abnormal endocytosis in the yolk sac visceral endoderm

Dendritic cell SIRPα regulates homeostasis of dendritic cells in lymphoid organs

Genetic dissection of dendritic cell homeostasis and function: lessons from cell type-specific gene ablation

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