The SNARE VAMP7 Regulates Exocytic Trafficking of Interleukin-12 in Dendritic Cells

Chiaruttini, Giulia; Piperno, Giulia Maria; Jouve, Mabel; Nardi, Francesca; Larghi, Paola; Peden, Andrew A.; Baj, Gabriele; Müller, Sabina; Valitutti, Salvatore; Galli, Thierry; Benvenuti, Federica

doi:10.1016/j.celrep.2016.02.055

Cited by 40 publications

(51 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the basis of the above findings, we reasoned that loss of antigen presentation in tumor-exposed DCs may depend on alteration of the finely tuned trafficking machinery that orchestrate antigen handling. Proteins of the SNARE and Rab family are important regulator of antigen-processing and cytokine secretion in DCs (16,(32)(33)(34). The importance of these pathways is undescored by SNARE downregulation by viruses as a mechanism of escape (35,36).…”

Section: Loss Of Membrane Trafficking Protein Leads To Defective Crosmentioning

confidence: 99%

“…Molecularly, this is ensured by highly regulated and cell-specific expression of membrane-trafficking proteins that together orchestrate slow acidification in phagosome and export of antigens to the cytosol (15). In addition, membrane trafficking proteins are important for secretion of antitumoral cytokines, such as IL12 (16). Vesicular soluble N-ethylmaleimide sensitive proteins (v-SNARE) allow fusion of membranes across the biosynthetic and exocytic route (17).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Downregulation of Membrane Trafficking Proteins and Lactate Conditioning Determine Loss of Dendritic Cell Function in Lung Cancer

et al. 2018

Self Cite

View full text Add to dashboard Cite

Restoring antigen presentation for efficient and durable activation of tumor-specific CD8 T-cell responses is pivotal to immunotherapy, yet the mechanisms that cause subversion of dendritic cell (DC) functions are not entirely understood, limiting the development of targeted approaches. In this study, we show that DCs resident in lung tumor tissues or DCs exposed to factors derived from whole lung tumors become refractory to endosomal and cytosolic sensor stimulation and fail to secrete IL12 and IFNI. Tumor-conditioned DC exhibited downregulation of the SNARE VAMP3, a regulator of endosomes trafficking critical for cross-presentation of tumor antigens and DC-mediated tumor rejection. Dissection of cell-extrinsic suppressive pathways identified lactic acid in the tumor microenvironment as sufficient to inhibit type-I IFN downstream of TLR3 and STING. DC conditioning by lactate also impacted adaptive function, accelerating antigen degradation and impairing cross-presentation. Importantly, DCs conditioned by lactate failed to prime antitumor responses These findings provide a new mechanistic viewpoint to the concept of DC suppression and hold potential for future therapeutic approaches. These findings provide insight into the cell-intrinsic and cell-extrinsic mechanisms that cause loss of presentation of tumor-specific antigens in lung cancer tissues. .

show abstract

Section: Loss Of Membrane Trafficking Protein Leads To Defective Crosmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Downregulation of Membrane Trafficking Proteins and Lactate Conditioning Determine Loss of Dendritic Cell Function in Lung Cancer

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…The effects of LRRK1 and VARP suggest that their concentration in the cell is important for VAMP7 center to periphery distribution, fitting well with the notion of a tug-of-war mechanism. In conclusion, we suggest that VAMP7 lysosomal secretion is regulated by biomechanical constraints relayed by LRRK1 and VARP, a mechanism with potential broad relevance for plasma membrane dynamics in normal conditions (Koseoglu et al, 2015), infection (Chiaruttini et al, 2016; Larghi et al, 2013) and cancer (Steffen et al, 2008).…”

Section: Discussionmentioning

confidence: 83%

Biomechanical control of lysosomal secretion via the VAMP7 hub: a tug-of-war mechanism between VARP and LRRK1

Wang

Nola

Bovio

et al. 2017

Preprint

Self Cite

View full text Add to dashboard Cite

16The rigidity of the cell environment can vary tremendously between tissues and in pathological conditions. 17How this property may affect intracellular membrane dynamics is still largely unknown. Here, using 18 atomic force microscopy, we found that cells deficient in the secretory lysosome v-SNARE VAMP7 were 19 impaired in adapting to substrate rigidity. Conversely VAMP7-mediated secretion was stimulated by more 20 rigid substrate and this regulation depended on the Longin domain of VAMP7. We further found that the 21Longin domain bound the kinase and retrograde trafficking adaptor LRRK1 and LRRK1 negatively 22 regulated VAMP7-mediated exocytosis. Conversely, VARP, a VAMP7-and kinesin 1-interacting protein, 23 further controlled the availability for secretion of peripheral VAMP7 vesicles and response of cells to 24 mechanical constraints. We propose a mechanism whereby biomechanical constraints regulate VAMP7-25 dependent lysosomal secretion via LRRK1 and VARP tug-of-war control of the peripheral readily-26 releasable pool of secretory lysosomes. 27 28 peer-reviewed)

show abstract

“…In fact, pivotal events for T cell priming such as MHC-II expression or IL-12 secretion toward T cell depend on DC polarization events. 3,17,18 The PDZ polarity proteins Scrib and Dlg1 have been involved in a wide range of T cell processes in the context of specific molecular segregation, hence in polarized events. 5,[19][20][21] Even though it is clear that the establishment of polarity in DCs is important, mechanisms that control DC polarized functions such as migration and Ag presentation have been scarcely studied.…”

Section: Introductionmentioning

confidence: 99%

Scrib and Dlg1 polarity proteins regulate Ag presentation in human dendritic cells

Barreda

Ramón‐Luing

Duran‐Luis

et al. 2020

Journal of Leukocyte Biology

View full text Add to dashboard Cite

We recently reported, for the first time, the expression and regulation of the PDZ polarity proteins Scrib and Dlg1 in human APCs, and also described the viral targeting of these proteins by NS1 of influenza A virus in human dendritic cells (DCs). Scrib plays an important role in reactive oxygen species (ROS) production in Mϕs and uropod formation and migration in T cells, while Dlg1 is important for T cell downstream activation after Ag recognition. Nevertheless, the functions of these proteins in human DCs remain unknown. Here, we knocked‐down the expression of both Scrib and Dlg1 in human DCs and then evaluated the expression of co‐stimulatory molecules and cytokine production during maturation. We demonstrated that Scrib is necessary for adequate CD86 expression, while Dlg1 is important for CD83 up‐regulation and IL‐6 production upon maturation, suggesting that Scrib and Dlg1 participate in separate pathways in DCs. Additionally, both proteins are required for adequate IL‐12 production after maturation. Furthermore, we showed that the inefficient maturation of DCs induced by Scrib or Dlg1 depletion leads to impaired T cell activation. Our results revealed the previously unknown contribution of Scrib and Dlg1 in human DCs pivotal functions, which may be able to impact innate and adaptive immune response.

show abstract

The SNARE VAMP7 Regulates Exocytic Trafficking of Interleukin-12 in Dendritic Cells

Cited by 40 publications

References 50 publications

Downregulation of Membrane Trafficking Proteins and Lactate Conditioning Determine Loss of Dendritic Cell Function in Lung Cancer

Downregulation of Membrane Trafficking Proteins and Lactate Conditioning Determine Loss of Dendritic Cell Function in Lung Cancer

Biomechanical control of lysosomal secretion via the VAMP7 hub: a tug-of-war mechanism between VARP and LRRK1

Scrib and Dlg1 polarity proteins regulate Ag presentation in human dendritic cells

Contact Info

Product

Resources

About