Synaptotagmin‐11 inhibits clathrin‐mediated and bulk endocytosis

Wang, Changhe; Wang, Yeshi; Hu, Meiru; Chai, Zuying; Wu, Qihui; Huang, Rong; Han, Weiping; Zhang, Claire Xi; Zhou, Zhuan

doi:10.15252/embr.201540689

Cited by 48 publications

(66 citation statements)

References 66 publications

(108 reference statements)

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“…In macrophages, Syt11 inhibits IL‐6 and TNF‐α secretion (Arango Duque et al, ), which is mediated by constitutive conventional exocytosis (Murray & Stow, ). Previously, we reported that Syt11 does not affect Ca 2+ ‐regulated evoked exocytosis in dorsal root ganglion and hippocampal neurons (Wang et al, ). Here, we report that Syt11 specifically inhibited the conventional secretion of IL‐6 and TNF‐α without affecting the unconventional secretion of IL‐1β or NO release (Figure ).…”

Section: Discussionmentioning

confidence: 88%

“…shSyt11‐resistant Syt11 expression construct (CMV‐myc‐Syt11‐IRES2‐BFP) for Rescue experiments were generated by introducing silent mutations as follows: ATG GCG GAA ATT ACC AAT ATA CG. A random sequence that was predicted to target no genes in human, rat, and mouse cells was chosen as a negative control (Wang et al, ). For Syt11 silencing or rescue experiments, microglia were processed 7 days after lentivirus infection.…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies have shown that Syt11 inhibits both endocytosis and exocytosis (Arango Duque et al, 2013;Sreetama et al, 2016;Wang et al, 2016). To dissect the regulation of Syt11 in cytokine exocytosis from increased cytokine synthesis due to microglial activation, we compared the extracellular cytokine levels with their intracellular levels to assess the capacity of cytokine secretion in primary microglia.…”

Section: Syt11 Regulates the Conventional Secretion Pathwaymentioning

confidence: 99%

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Synaptotagmin‐11 inhibits cytokine secretion and phagocytosis in microglia

Wang

Zhang

et al. 2017

Glia

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Cytokine secretion and phagocytosis are key functions of activated microglia. However, the molecular mechanisms underlying their regulation in microglia remain largely unknown. Here, we report that synaptotagmin-11 (Syt11), a non-Ca -binding Syt implicated in Parkinson disease and schizophrenia, inhibits cytokine secretion and phagocytosis in microglia. We found Syt11 expression in microglia in brain slices and primary microglia. Interestingly, Syt11-knockdown (KD) increased cytokine secretion and NO release in primary microglia both in the absence and presence of lipopolysaccharide. NF-κB was activated in untreated KD microglia together with enhanced synthesis of IL-6, TNF-α, IL-1β, and iNOS. When the release capacity was assessed by the ratio of extracellular to intracellular levels, only the IL-6 and TNF-α secretion capacity was increased in Syt11-KD cells, suggesting that Syt11 specifically regulates conventional secretion. Consistently, Syt11 localized to the trans-Golgi network and recycling endosomes. In addition, Syt11 was recruited to phagosomes and its deficiency enhanced microglial phagocytosis. All the KD phenotypes were rescued by expression of an shRNA-resistant Syt11, while overexpression of Syt11 suppressed cytokine secretion and phagocytosis. Importantly, Syt11 also inhibited microglial phagocytosis of α-synuclein fibrils, supporting its association with Parkinson disease. Taken together, we propose that Syt11 suppresses microglial activation under both physiological and pathological conditions through the inhibition of cytokine secretion and phagocytosis.

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Section: Discussionmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Section: Syt11 Regulates the Conventional Secretion Pathwaymentioning

confidence: 99%

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Synaptotagmin‐11 inhibits cytokine secretion and phagocytosis in microglia

Wang

Zhang

et al. 2017

Glia

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“…EM imaging. EM of adrenal slices was performed according to previous descriptions with minor modifications (de Wit et al, 2009a;Wang et al, 2016). The adrenal glands were extracted from adult WT and dyn1-KO mice and then the adrenal cortex was removed and the medulla was cut into 1-2 mm 3 pieces.…”

Section: Methodsmentioning

confidence: 99%

Dynamin 1 Restrains Vesicular Release to a Subquantal Mode In Mammalian Adrenal Chromaffin Cells

Zhang

Liu

et al. 2018

J. Neurosci.

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Dynamin 1 (dyn1) is required for clathrin-mediated endocytosis in most secretory (neuronal and neuroendocrine) cells. There are two modes of Ca 2ϩ -dependent catecholamine release from single dense-core vesicles: full-quantal (quantal) and subquantal in adrenal chromaffin cells, but their relative occurrences and impacts on total secretion remain unclear. To address this fundamental question in neurotransmission area using both sexes of animals, here we report the following: (1) dyn1-KO increased quantal size (QS, but not vesicle size/content) by Ն250% in dyn1-KO mice; (2) the KO-increased QS was rescued by dyn1 (but not its deficient mutant or dyn2); (3) the ratio of quantal versus subquantal events was increased by KO; (4) following a release event, more protein contents were retained in WT versus KO vesicles; and (5) the fusion pore size (d p ) was increased from Յ9 to Ն9 nm by KO. Therefore, Ca 2ϩ -induced exocytosis is generally a subquantal release in sympathetic adrenal chromaffin cells, implying that neurotransmitter release is generally regulated by dynamin in neuronal cells. Ca 2ϩ -dependent neurotransmitter release from a single vesicle is the primary event in all neurotransmission, including synaptic/ neuroendocrine forms. To determine whether Ca 2ϩ -dependent vesicular neurotransmitter release is "all-or-none" (quantal), we provide compelling evidence that most Ca 2ϩ -induced secretory events occur via the subquantal mode in native adrenal chromaffin cells. This subquantal release mode is promoted by dynamin 1, which is universally required for most secretory cells, including neurons and neuroendocrine cells. The present work with dyn1-KO mice further confirms that Ca 2ϩ -dependent transmitter release is mainly via subquantal mode, suggesting that subquantal release could be also important in other types of cells.

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“…26,37 Previously, we discovered that Syt11 inhibits clathrin-mediated and bulk endocytosis in neurons as well as cytokine secretion and phagocytosis in microglia. 38,39 Here, we report that Syt11 also inhibited caveolae-mediated endocytosis, most likely via direct interactions with cavin1 and EHD2, but not Cav1. Surprisingly, we discovered that Syt11 positively regulated the mechanosensitive and mechanoprotective functions of caveolae and astrocyte swelling.…”

Section: Introductionmentioning

confidence: 68%

Synaptotagmin‐11 regulates the functions of caveolae and responds to mechanical stimuli in astrocytes

et al. 2019

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Abbreviations: Cav, caveolin; EHD2, EH domain-containing protein 2; Flot-1, flotillin-1; LacCer, BODIPY FL C5-Lactosylceramide; Syt11, synaptotagmin-11; TfR, transferrin receptor. AbstractCaveolae play crucial roles in intracellular membrane trafficking and mechanosensation. In this study, we report that synaptotagmin-11 (Syt11), a synaptotagmin isoform associated with Parkinson's disease and schizophrenia, regulates both caveolaemediated endocytosis and the caveolar response to mechanical stimuli in astrocytes.Syt11-knockout (KO) accelerated caveolae-mediated endocytosis. Interestingly, the caveolar structures on the cell surface were markedly fewer in the absence of Syt11.Caveolar disassembly in response to hypoosmotic stimuli and astrocyte swelling were both impaired in Syt11-KO astrocytes. Live imaging revealed that Syt11 left caveolar structures before cavin1 during hypoosmotic stress and returned earlier than cavin1 after isoosmotic recovery. Chronic hypoosmotic stress led to proteasomemediated Syt11 degradation. In addition, Syt11-KO increased the turnover of cavin1 and EH domain-containing protein 2 (EHD2), accompanied by compromised membrane integrity, suggesting a mechanoprotective role of Syt11. Direct interactions between Syt11 and cavin1 and EHD2, but not caveolin-1, are found. Altogether, we propose that Syt11 stabilizes caveolar structures on the cell surface of astrocytes and regulates caveolar functions under physiological and pathological conditions through cavin1 and EHD2. K E Y W O R D Sastrocyte swelling, endocytosis, hypoosmotic stress, mechanoprotection 2610 | YAN et Al.

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Synaptotagmin‐11 inhibits clathrin‐mediated and bulk endocytosis

Cited by 48 publications

References 66 publications

Synaptotagmin‐11 inhibits cytokine secretion and phagocytosis in microglia

Synaptotagmin‐11 inhibits cytokine secretion and phagocytosis in microglia

Dynamin 1 Restrains Vesicular Release to a Subquantal Mode In Mammalian Adrenal Chromaffin Cells

Synaptotagmin‐11 regulates the functions of caveolae and responds to mechanical stimuli in astrocytes

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