Asna1/TRC40 Controls β-Cell Function and Endoplasmic Reticulum Homeostasis by Ensuring Retrograde Transport

Abstract

Type 2 diabetes (T2D) is characterized by insulin resistance and β-cell failure. Insulin resistance per se, however, does not provoke overt diabetes as long as compensatory β-cell function is maintained. The increased demand for insulin stresses the β-cell endoplasmic reticulum (ER) and secretory pathway, and ER stress is associated with β-cell failure in T2D. The tail recognition complex (TRC) pathway, including Asna1/TRC40, is implicated in the maintenance of endomembrane trafficking and ER homeostasis. To gain insight into the role of Asna1/TRC40 in maintaining endomembrane homeostasis and β-cell function, we inactivated Asna1 in β-cells of mice. We show that Asna1β−/− mice develop hypoinsulinemia, impaired insulin secretion, and glucose intolerance that rapidly progresses to overt diabetes. Loss of Asna1 function leads to perturbed plasma membrane-to-trans Golgi network and Golgi-to-ER retrograde transport as well as to ER stress in β-cells. Of note, pharmacological inhibition of retrograde transport in isolated islets and insulinoma cells mimicked the phenotype of Asna1β−/− β-cells and resulted in reduced insulin content and ER stress. These data support a model where Asna1 ensures retrograde transport and, hence, ER and insulin homeostasis in β-cells.

Mice lacking WRB reveal differential biogenesis requirements of tail-anchored proteins in vivo

“…4a,b). These strong general effects on the integrity of the liver support previous observations of the essential functions of TRC40 pathway in development and tissue homeostasis212223252930. In contrast to enzymatic activities indicating liver damage, the serological levels of cholesterol and triglycerides in Cre-positive animals did not change significantly in comparison to control littermates (Supplementary Fig.…”

“…Generation of conditional knockouts restricted to specific cell types allows the identification of relevant functions of components of the TRC40 pathway in tissue development and physiology. A recent study revealed that pancreatic beta cells lacking TRC40 show impaired insulin secretion23, whereas CAML is required for thymocyte development24, and loss of either receptor subunit in inner ear cells causes deafness2526.…”

Loss of GET pathway orthologs in Arabidopsis thaliana causes root hair growth defects and affects SNARE abundance

“…Taken together, our findings indicate feedback control, where loss of AtGET function and the resulting failure of SYP123 protein insertion activate inhibition at the transcript level to decrease steady-state levels of both mRNA and protein. Functional cross-talk between the GET pathway and its impact on transcript regulation had been shown previously in other eukaryotes (23,49).…”

“…Conversely, lack of the mammalian GET3 orthologs TRC40 (transmembrane domain recognition complex of 40 kDa) leads to embryo lethality in mice, complicating global physiological analyses (21). Nevertheless, a handful of recent studies have started to analyze individual physiological consequences of the GET pathway in vivo using tissue-specific knockout (KO) approaches and observed that its function is required for a diverse range of physiological processes, such as insulin secretion, auditory perception, and photoreceptor function, in animals (22)(23)(24). A high degree of evolutionary conservation is often assumed, and it has been recognized that some components of the GET pathway are present in Arabidopsis thaliana (25,26).…”

Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells

“…These genes are regulated by XBP1s [24,25] and are correlated with Xbp1 mRNA splicing following glucose stimulation in beta cells [43]. A recent study showed that impaired Golgi-to-ER retrograde transport can induce beta cell ER stress [44]. Moreover, blockage of ER-to-Golgi protein trafficking causes accumulation of proteins in the ER and thus ER stress in beta cells chronically exposed to saturated fatty acids [21,22,45].…”