The tetraspanin CD63 is involved in granule targeting of neutrophil elastase

Källquist, Linda; Hansson, Markus; Persson, Ann-Maj; Janssen, Hans; Calafat, Jero; Tapper, Hans; Olsson, Inge

doi:10.1182/blood-2007-10-116285

Cited by 44 publications

(28 citation statements)

References 42 publications

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“…Our and other published data (Kallquist et al, 2008; Michaux and Cutler, 2004) show that CD63 in specialized cells is predominantly associated with LROs and their endosomal precursors, suggesting a specific role in LRO formation and/or function as proposed (Pols and Klumperman, 2009). Consistently, whereas lysosomal defects are not detected in CD63 knockout mice (Schroder et al, 2009), these mice do harbor altered LROs, as shown here for melanosomes.…”

Section: Discussionsupporting

confidence: 80%

The Tetraspanin CD63 Regulates ESCRT-Independent and -Dependent Endosomal Sorting during Melanogenesis

et al. 2011

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Summary Cargo sorting to intraluminal vesicles (ILVs) of multivesicular endosomes is required for numerous physiological processes including lysosome-related organelle (LRO) biogenesis. PMEL – a component of melanocyte LROs (melanosomes) – is sorted to ILVs in an ESCRT-independent manner, where it is proteolytically processed and assembled into functional amyloid fibrils during melanosome maturation. Here we show that the tetraspanin CD63 directly participates in ESCRT-independent sorting of the PMEL luminal domain, but not of traditional ESCRT-dependent cargoes, to ILVs. Inactivating CD63 in cell culture or in mice impairs amyloidogenesis and downstream melanosome morphogenesis. Whereas CD63 is required for normal PMEL luminal domain sorting, the disposal of the remaining PMEL transmembrane fragment requires functional ESCRTs but not CD63. In the absence of CD63, the PMEL luminal domain follows this fragment and is targeted for ESCRT-dependent degradation. Our data thus reveal a tight interplay regulated by CD63 between two distinct endosomal ILV sorting processes for a single cargo during LRO biogenesis.

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Section: Discussionsupporting

confidence: 80%

The Tetraspanin CD63 Regulates ESCRT-Independent and -Dependent Endosomal Sorting during Melanogenesis

et al. 2011

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“…CD63, an abundant membrane protein of primary granules, is sorted by AP-3, and has been shown to play a role in granule protein quality control since it can be trafficked from many membranes to granules (40, 41). A recent study showed that CD63 and neutrophil elastase are present in a complex, highly indicative of a role for CD63 in the targeting of elastase to primary granules (42). Other serine proteases affected by CD63 granule sorting include proteinase-3 (39), and possibly the cathepsin family of proteases, which exhibit varying degrees of M6P-dependent/independent sorting (36, 43–45).…”

Section: Neutrophil Granularitymentioning

confidence: 99%

Granule Protein Processing and Regulated Secretion in Neutrophils

et al. 2014

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Neutrophils are part of a family of granulocytes that, together with eosinophils and basophils, play an essential role in innate immunity. Neutrophils are the most abundant circulating leukocytes and are vital for rapid immune responses, being recruited to sites of injury or infection within minutes, where they can act as specialized phagocytic cells. However, another prominent function of neutrophils is the release of pro-inflammatory compounds, including cytokines, chemokines, and digestive enzymes, which are stored in intracellular compartments and released through regulated exocytosis. Hence, an important feature that contributes to rapid immune responses is capacity of neutrophils to synthesize and store pre-formed pro-inflammatory mediators in specialized intracellular vesicles and thus no new synthesis is required. This review will focus on advancement in three topics relevant to neutrophil secretion. First, we will examine what is known about basal level pro-inflammatory mediator synthesis, trafficking, and storage in secretory compartments. Second, we will review recent advancements in the mechanisms that control vesicle mobilization and the release of pre-formed mediators. Third, we will examine the upregulation and de novo synthesis of pro-inflammatory mediators by neutrophils engaged at sites of infection.

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“…It is, therefore, likely that TIMP-1 directly acts on hematopoietic progenitors, triggering their differentiation towards the granulocytic lineage. As CD63 itself is described to regulate activation and adhesion of mature neutrophils to endothelium, 51 granule targeting and release, 52 and is up-regulated on apoptotic neutrophils, 53 TIMP-1 /CD63 interactions may have additional effects on mature neutrophils.Our observations were made on mice, where neutrophil blood counts are generally lower than in humans. 34 Therefore, it remains to be shown whether high TIMP-1 levels have a similar effect on the human hematopoietic system.…”

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confidence: 99%

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confidence: 99%

TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nrent study, we investigated whether TIMP-1 affects neutrophil homeostasis. We show that TIMP-1 signaling via CD63 triggered granulopoiesis in the bone marrow (BM) resulting in increased systemic neutrophil blood counts. Our findings reveal a new function of TIMP-1 on immune cell homeostasis, and may provide a link to the frequently described correlation of high TIMP-1 levels with inflammatory diseases in the clinic. Methods Animal experimentsAnimal experiments were performed in compliance with the guidelines of the Tierschutzgesetz des Freistaates Bayern and approved by the Regierung von Oberbayern. For TIMP-1-secreting tumors, 2x10 6 HT1080 cells were subcutaneously injected into the nuchal fold of CD1 nu/nu mice and tumors were grown over ten days to a diameter of approximately 1 cm. Tumor size was monitored with a caliper. For adenoviral transduction, 3x10 9 ifu were intravenously injected, as previously described. 22 Recombinant TIMP-1 protein was applied in LPS-free PBS by a single intraperitoneal (i.p.) injection of 2 mg/kg, as previously described. 22 Mice were killed with CO 2 , blood was collected from the vena cava inferior using EDTA-coated syringes, and BM cells were obtained by flushing femurs and tibias with PBS. Flow cytometryAbsolute quantification of blood neutrophils occurred in BD trucount TM tubes according to the manufacturer´s instructions. Briefly, antibody-cocktail was mixed with 50 mL fresh blood in trucount TM tubes and incubated for 15 min at RT. Subsequently, 450 mL FACS TM lysing solution (BD Bioscience) were added and incubated for 30 min at RT to lyse erythrocytes and fix the sample. For staining of BM, femurs and tibias were flushed with PBS and the obtained cell suspension was stained as blood. Samples were measured on a FACS Canto TM II flow cytometer (BD) and analyzed using FlowJo software. Immunohistochemical staining of neutrophilsFor immunohistochemical analysis of BM, femurs were freed from tissue, fixed in 4% paraformaldehyde for 20 h, de-calcified in 0.5 M EDTA for five days, dehydrated and embedded into paraffin. Ly6G-positive cells were stained on 4 mm sections, as previously described. 22 Colony formation assayBone marrow cells were harvested from AdCtrl or AdT1-transduced mice and erythrocytes were removed with RBC lysis buffer (eBioscience). 1x10 4 BM cells were seeded in MethoCult TM medium (StemCell Technologies) containing 50 ng/mL murine rSCF, 10 ng/mL murine rIL-3, and 10 ng/mL murine rIL-6 into 6-well plates. Cells were incubated at 37°C for seven days and colonies per well were counted. For each mouse, analysis was performed in duplicates, and a total of 5 mice per group were analyzed. 32Dcl3 differentiation assay 32Dcl3 cells were seeded at a density of 8x10 5 cells/mL in IL3-free medium supplemented with 100 ng/mL murine G-CSF (Peptrotech) +/-1000 ng/mL rTIMP-1. Every two days, medium was replaced by fresh medium containing 50 ng/mL G-CSF +/-1000 ng/mL rTIMP-1. At the indicated time points, cells were c...

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The tetraspanin CD63 is involved in granule targeting of neutrophil elastase

Cited by 44 publications

References 42 publications

The Tetraspanin CD63 Regulates ESCRT-Independent and -Dependent Endosomal Sorting during Melanogenesis

The Tetraspanin CD63 Regulates ESCRT-Independent and -Dependent Endosomal Sorting during Melanogenesis

Granule Protein Processing and Regulated Secretion in Neutrophils

TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice

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