No abstract

The endoplasmic reticulum (ER) is an organelle equipped with mechanisms for proper protein folding, trafficking, and degradation to maintain protein homeostasis in the secretory pathway. As a defense mechanism, perturbation of ER proteostasis by ER stress agents activates a cascade of signaling pathways from the ER to the nucleus known as unfolded protein response (UPR). The primary goal of UPR is to induce transcriptional and translational programs to restore ER homeostasis for cell survival. As such, defects in UPR signaling have been implicated as a key contributor to multiple diseases including metabolic diseases, degenerative diseases, inflammatory disorders, and cancer. Growing evidence support the critical role of ER stress in regulating the fate as well as the magnitude of the immune response. Moreover, the availability of multiple UPR pharmacological inhibitors raises the hope that targeting UPR can be a new strategy for immune modulation and immunotherapy of diseases. This paper reviews the principal mechanisms by which ER stress affects immune cell biology and function, with a focus of discussion on UPR-associated immunopathology and the development of potential ER stress-targeted therapeutics.Frontiers in Immunology | www.frontiersin.org Conflict of Interest: ZL serves as member of scientific advisory board for Alphamab and Henlius Biotech and has a sponsored research agreement with Bristol-Myers Squibb.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Sex bias exists in the development and progression of non-reproductive organ cancers, but the underlying mechanisms are enigmatic. Studies so far have focused largely on sexual dimorphisms in cancer biology and socioeconomic factors. Here, we establish a role for CD8 + T cell-dependent anti-tumor immunity in mediating sex differences in tumor aggressiveness, which is driven by the gonadal androgen but not sex chromosomes. A male bias exists in the frequency of intratumoral antigen-experienced Tcf7 /TCF1 + progenitor exhausted CD8 + T cells that are devoid of effector activity as a consequence of intrinsic androgen receptor (AR) function. Mechanistically, we identify a novel sex-specific regulon in progenitor exhausted CD8 + T cells and a pertinent contribution from AR as a direct transcriptional trans-activator of Tcf7 /TCF1. The T cell intrinsic function of AR in promoting CD8 + T cell exhaustion in vivo was established using multiple approaches including loss-of-function studies with CD8-specific Ar knockout mice. Moreover, ablation of the androgen-AR axis rewires the tumor microenvironment to favor effector T cell differentiation and potentiates the efficacy of anti-PD-1 immune checkpoint blockade. Collectively, our findings highlight androgen-mediated promotion of CD8 + T cell dysfunction in cancer and imply broader opportunities for therapeutic development from understanding sex disparities in health and disease.

Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into mature cells of various cell types. Although the differentiation process of MSCs requires lineage-specific transcription factors, the exact molecular mechanism that determines MSCs differentiation is not clearly addressed. Here, we demonstrate a Smad4-Taz axis as a new intrinsic regulator for adipoosteogenic differentiation of MSCs and show that this function of Smad4 is independent of the transforming growth factor-β signal. Smad4 directly bound to the Taz protein and facilitated nuclear localization of Taz through its nuclear localization signal. Nuclear retention of Taz by direct binding to Smad4 increased expression of osteogenic genes through enhancing Taz-runt-related transcription factor 2 (Runx2) interactions in the C3H10T1/2 MSC cell line and preosteoblastic MC3T3-E1 cells, whereas it suppressed expression of adipogenic genes through promoting Tazperoxisome proliferator-activated receptor-γ (PPARγ) interaction in C3H10T1/2 and preadipogenic 3T3-L1 cells. A reciprocal role of the Smad4 in osteogenic and adipogenic differentiation was also observed in human adipose tissue-derived stem cells (hASCs). Consequently, Smad4 depletion in C3H10T1/2 and hASCs reduced nuclear retention of Taz and thus caused the decreased interaction with Runx2 or PPARγ, resulting in delayed osteogenesis or enhanced adipogenesis of the MSC. Therefore, these findings provide insight into a novel function of Smad4 to regulate the balance of MSC lineage commitment through reciprocal targeting of the Taz protein in osteogenic and adipogenic differentiation pathways. STEM CELLS 2019;37:368-381 SIGNIFICANCE STATEMENTAlthough the Smad4 protein has been suggested to act as a common Smad in the transforming growth factor-β (TGF-ß) superfamily signaling pathway in human embryonic stem cells, it has been unclear whether Smad4 has a noncanonical role in adipo-osteogenic differentiation of mesenchymal stem cells (MSCs), independent of the TGF-ß and bone morphogenic protein pathways. The study demonstrated that Smad4 plays a crucial role in the regulation of lineage commitment of the MSCs, including human adipose tissue-derived stem cells, into osteoblasts and adipocytes through modulating the retention of Taz in the nucleus during MSC differentiation. The Smad4 is specific to Taz but not YAP. Therefore, the findings provide new insight into a novel mechanism of the Smad4-Taz axis in adipo-osteogenic differentiation of MSCs and demonstrate a reciprocal role of Smad4 as a positive and negative factor in osteogenesis and adipogenesis of MSCs, respectively.

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The growing focus on brown adipocytes has spurred an interest in their potential benefits for metabolic diseases. Brown and beige (or brite) adipocytes express high levels of uncoupling protein 1 (Ucp1) to dissipate heat instead of generating ATP. Ucp1 induction by stimuli including cold, exercise, and diet increases nonshivering thermogenesis, leading to increased energy expenditure and prevention of obesity. Recently, studies in adipocytes have indicated the existence of functional Ucp1-independent thermogenic regulators. Furthermore, substrate cycling involving creatine metabolites, cold-induced N-acyl amino acids, and oxidized lipids in white adipocytes can increase energy expenditure in the absence of Ucp1. These studies emphasize the need for a better understanding of the mechanisms governing energy expenditure in adipocytes and their potential applications in the prevention of human obesity and metabolic diseases. KEYWORDS adipocyte, energy expenditure, obesity, Ucp1 1 | GLOBAL EPIDEMIC OF OBESITY By 2030, approximately 57.8% (3.3 billion) of the adult population throughout the world could be obese or overweight. 1 The global epidemic of obesity could cause various diseases, including liver disease, diabetes, cardiovascular disease, and cancer. 2 Obesity is characterizedby an accumulation of excess energy as triglycerides and occurs when the overall energy intake surpasses energy expenditure. Appetite suppression by pharmacological means is considered to be one approach to prevent obesity. However, this treatment has several side effects, most of which are related to the nervous system. 3 Inhibiting the absorption of dietary fat in the intestine is another approach. Unfortunately, it is associated with diarrhea, headache, and nausea 4,5 Recent efforts have focused on the manipulation of thermogenic brown adipocytes as a means to increase energy expenditure and develop a promising new strategy for ameliorating obesity and metabolic diseases. [6][7][8] In particular, the discovery of active brown adipocytes in the human body encouraged increases in energy expenditure as an excellent alternative for treating human obesity and metabolic diseases. 9-11 Here, we review thermogenesis in adipocytes and further discuss the importance of functional uncoupling protein 1 (Ucp1)dependent and Ucp1-independent thermogenic stimulators (Table 1).

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Notch signaling pathways modulate various cellular processes, including cell proliferation, differentiation, adhesion, and communication. Recent studies have demonstrated that Notch1 signaling also regulates hepatic glucose production and lipid synthesis. However, the effect of Notch1 signaling on hepatic lipid oxidation has not yet been directly investigated. To define the function of Notch1 signaling in hepatic lipid metabolism, wild type mice and Notch1 deficient antisense transgenic (NAS) mice were fed a high-fat diet. High-fat diet -fed NAS mice exhibited a marked reduction in hepatic triacylglycerol accumulation compared with wild type obese mice. The improved fatty liver was associated with an increased expression of hepatic genes involved in fatty acid oxidation. However, lipogenic genes were not differentially expressed in the NAS liver, suggesting lipolytic-specific regulatory effects by Notch1 signaling. Expression of fatty acid oxidative genes and the rate of fatty acid oxidation were also increased by inhibition of Notch1 signaling in HepG2 cells. In addition, similar regulatory effects on lipid accumulation were observed in adipocytes. Taken together, these data show that inhibition of Notch1 signaling can regulate the expression of fatty acid oxidation genes and may provide therapeutic strategies in obesity-induced hepatic steatosis.