SIDT2 is involved in the NAADP-mediated release of calcium from insulin secretory granules

Chang, Guoying; Yang, Rui; Cao, Yanan; Nie, Aifang; Gu, Xuefan; Zhang, Huiwen

doi:10.1530/jme-15-0227

Cited by 23 publications

(15 citation statements)

References 41 publications

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“…Sidt2‐deficient mice express reduced levels of the SNARE proteins synap1 and synap3 indicating that Sidt2 and SNAREs are directly involved in insulin secretion . Furthermore, the intracellular calcium signaling was changed in primary pancreatic β‐cells, this effect could be reversed by bafilomycin connecting intracellular calcium signaling to lysosomes . Application of nicotinic acid adenine dinucleotide phosphate (NAADP) rescued the calcium response although the islets of Sidt2‐deficient mice synthesized NAADP normally.…”

Section: Discussionmentioning

confidence: 99%

Identification of Sidt2 as a lysosomal cation‐conducting protein

et al. 2017

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A screen to identify lysosomal‐expressed ion channels led to the discovery of the human Sidt2 protein. Sidt2 is expressed within lysosomal organelles but as a result of heterologous overexpression the protein is also detectable within the plasma membrane of human embryonic kidney cells. The overexpressed protein leads to cell depolarization upon sodium addition. Accordingly in whole‐cell patch clamp experiments a spontaneous noninactivating monovalent cation current can be detected in Sidt2‐overexpressing cells. Strong overexpression of Sidt2 in HEK293 cells is attended by a significant reduction/loss of detectable lysosomes, indicating that the overexpressed protein leads to lysosomal dysfunction, a hallmark of Alzheimer's disease. Sidt2 is located on chromosome 11q23, a locus repeatedly found by chromosomal mapping of Alzheimer's disease‐related genes.

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Section: Discussionmentioning

confidence: 99%

Identification of Sidt2 as a lysosomal cation‐conducting protein

et al. 2017

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“…On the other hand, some studies have observed physiological effects of SIDT2 where the relationship to RNA transport, if any, is unclear. For example, mice lacking SIDT2 demonstrate impaired glucose tolerance, decreased serum insulin levels, and defective insulin secretion (Chang et al., 2016, Gao et al., 2013, Yu et al., 2015). Two recent studies also demonstrated that Sidt2 −/− mice develop non-alcoholic fatty liver disease (Chen et al., 2018, Gao et al., 2016), with one suggesting that this is due to induction of endoplasmic reticulum stress (Gao et al., 2016) and the other proposing that it is the result of defective autophagy (Chen et al., 2018).…”

Section: Introductionmentioning

confidence: 99%

SIDT2 RNA Transporter Promotes Lung and Gastrointestinal Tumor Development

et al. 2019

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SummaryRNautophagy is a newly described type of selective autophagy whereby cellular RNAs are transported into lysosomes for degradation. This process involves the transmembrane protein SIDT2, which transports double-stranded RNA (dsRNA) across the endolysosomal membrane. We previously demonstrated that SIDT2 is a transcriptional target of p53, but its role in tumorigenesis, if any, is unclear. Unexpectedly, we show here that Sidt2−/− mice with concurrent oncogenic KrasG12D activation develop significantly fewer tumors than littermate controls in a mouse model of lung adenocarcinoma. Consistent with this observation, loss of SIDT2 also leads to enhanced survival and delayed tumor development in an Apcmin/+ mouse model of intestinal cancer. Within the intestine, Apcmin/+;Sidt2−/− mice display accumulation of dsRNA in association with increased phosphorylation of eIF2α and JNK as well as elevated rates of apoptosis. Taken together, our data demonstrate a role for SIDT2, and by extension RNautophagy, in promoting tumor development.

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“…NAADP is a potent signaling molecule produced during β-cell glucose metabolism [ 280 ] that binds to unidentified NAADP-sensitive sites to elicit Ca 2+ release from intracellular stores, including the SG, during GSIS [ 31 , 281 ]. SIDT2 is located on insulin SGs and may mediate this mechanism [ 281 ]. Whole-body SIDT2 KO mice are glucose intolerant and have an insulin secretory defect [ 282 ].…”

Section: Luminal Components Of the Insulin Secretory Granulementioning

confidence: 99%

Inside the Insulin Secretory Granule

et al. 2021

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The pancreatic β-cell is purpose-built for the production and secretion of insulin, the only hormone that can remove glucose from the bloodstream. Insulin is kept inside miniature membrane-bound storage compartments known as secretory granules (SGs), and these specialized organelles can readily fuse with the plasma membrane upon cellular stimulation to release insulin. Insulin is synthesized in the endoplasmic reticulum (ER) as a biologically inactive precursor, proinsulin, along with several other proteins that will also become members of the insulin SG. Their coordinated synthesis enables synchronized transit through the ER and Golgi apparatus for congregation at the trans-Golgi network, the initiating site of SG biogenesis. Here, proinsulin and its constituents enter the SG where conditions are optimized for proinsulin processing into insulin and subsequent insulin storage. A healthy β-cell is continually generating SGs to supply insulin in vast excess to what is secreted. Conversely, in type 2 diabetes (T2D), the inability of failing β-cells to secrete may be due to the limited biosynthesis of new insulin. Factors that drive the formation and maturation of SGs and thus the production of insulin are therefore critical for systemic glucose control. Here, we detail the formative hours of the insulin SG from the luminal perspective. We do this by mapping the journey of individual members of the SG as they contribute to its genesis.

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SIDT2 is involved in the NAADP-mediated release of calcium from insulin secretory granules

Cited by 23 publications

References 41 publications

Identification of Sidt2 as a lysosomal cation‐conducting protein

Identification of Sidt2 as a lysosomal cation‐conducting protein

SIDT2 RNA Transporter Promotes Lung and Gastrointestinal Tumor Development

Inside the Insulin Secretory Granule

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