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  • AACOCF3 mg br Challenges and open questions Deepening our un

    2022-01-21


    Challenges and open questions Deepening our understanding of PKC’s role in GSIS will require harnessing recently developed techniques and developing new tools. Here we describe three challenges remaining in the field and offer suggestions on experimental approaches to address them. PKC plays an important role in modulating insulin secretion from pancreatic beta cells. Dysfunctional PKC signaling may be one mechanistic cause of diabetic phenotypes in model organisms for the disease, which underscores the importance of fully understanding PKC’s contribution to the complex regulation of insulin release. PKC appears to act in multiple steps of GSIS, importantly both at the cortical AACOCF3 mg network and at the level of individual exocytotic proteins that play key roles in mediating membrane fusion. With advances in targeted phospho-proteomics and live-cell super resolution fluorescence microscopy, we can move towards a unified AACOCF3 mg model for how PKC acts at multiple sites in vivo to potentiate insulin secretion. Future work on PKC could lead to novel therapies or drugs to target exocytosis in the hopes of curing diabetes and other endocrine diseases.
    Acknowledgements We thank Ethan Tyler from the NIH Medical Arts Design Section for preparation of Fig. 1. We thank Thaddeus Davenport and Agila Somasundaram for critical reading of the manuscript and all members of the Taraska lab for helpful discussions. JWT is supported by the Intramural Research Program of the National Heart Lung and Blood Institute, National Institutes of Health.
    Introduction Lysosomal exocytosis has been originally described as a means of repairing plasma membrane via recruitment of the lysosomal membrane to a place of membrane damage [1]. Lysosomal fusion with the plasma membrane depends on a specific set of SNARE components [2], suggesting a regulated process. Therefore, the significance of lysosomal exocytosis likely extends beyond pathological conditions of membrane rupture, possibly including response, adaptation, or signaling involvement. The latter idea finds support in the recent series of evidence on the role of lysosomes in transition metal extraction from cells [3], [4]. Transition metals such as Fe, Zn and Cu enter cells via plasma membrane transporters or via endocytosis followed by absorption through lysosomal/endosomal transporters [5], [6], [7]. While all cells require some levels of transition metals, an excessive exposure to transition metals is toxic, necessitating their tight regulation. In the cytoplasm, transition metals are bound to chelating proteins, exported via plasma membrane transporters or absorbed into organelles, which is followed by exocytosis or metal-filled organelles. Among the transporters implicated into transition metals absorption into lysosomes are Zn transporters ZnT2 and ZnT4 (SLC30A2 and SLC30A4), and a Cu transporter ATP7B. Suppression of these transporters was shown to significantly affect Zn and Cu handling [3], [4]. Lysosomal transition metal importers are regulated in a variety of ways. ATP7B, the Cu transporter whose loss is responsible for Wilson's disease [8], responds to Cu exposure by moving from trans-Golgi to the lysosomes [3], [9]. Cu absorption by the lysosomes is followed by its extraction from the cells via SNARE-dependent lysosomal exocytosis [3]. Thus, the main mechanism of ATP7B regulation appears to be translocation to the lysosomes or perhaps formation of the new population of ATP7B-bearing lysosomes. In addition, ATP7B interacts with p62 subunit of dynactin facilitating lysosomal transport toward the apical pole of hepatic cell where Cu is released [3]. ZnT transporters, especially ZnT2, have been shown to translocate to the lysosomes in response or in parallel to Zn exposure, and structural determinants of such translocation have been proposed [10]. At the same time, transcription of genes coding for several ZnTs is regulated by the transcription factor MTF-1, which responds to Zn and other transition metals [11]. These data show that lysosomal metal uptake capacity is regulated by the cytoplasmic transition metals. Whether or not Cu regulates the rate of the lysosomal metal extraction has not been consistently explored. It is the main question of the present studies.