bims-stacyt 2023-04-23 papers

Immunohorizons. 2023 Apr 01. 7(4): 256-264

How the Unfolded Protein Response Is a Boon for Tumors and a Bane for the Immune System.

Lydia N Raines, Stanley Ching-Cheng Huang.

The correct folding of proteins is essential for appropriate cell function and is tightly regulated within the endoplasmic reticulum (ER). Environmental challenges and cellular conditions disrupt ER homeostasis and induce ER stress, which adversely affect protein folding and activate the unfolded protein response (UPR). It is now becoming recognized that cancer cells can overcome survival challenges posed within the tumor microenvironment by activating the UPR. Furthermore, the UPR has also been found to impose detrimental effects on immune cells by inducing immunoinhibitory activity in both tumor-infiltrating innate and adaptive immune cells. This suggests that these signaling axes may be important therapeutic targets, resulting in multifaceted approaches to eradicating tumor cells. In this mini-review, we discuss the role of the UPR in driving tumor progression and modulating the immune system's ability to target cancer cells. Additionally, we highlight some of the key unanswered questions that may steer future UPR research.

DOI: https://doi.org/10.4049/immunohorizons.2200064

Trends Biochem Sci. 2023 Apr 18. pii: S0968-0004(23)00080-4. [Epub ahead of print]

The metabolic cross-talk between cancer and T cells.

Silvia Cadenas-De Miguel, Giulia Lucianer, Ilaria Elia.

The metabolic cross-talk between cancer cells and T cells dictates cancer formation and progression. These cells possess metabolic plasticity. Thus, they adapt their metabolic profile to meet their phenotypic requirements. However, the nutrient microenvironment of a tumor is a very hostile niche in which these cells are forced to compete for the available nutrients. The hyperactive metabolism of tumor cells often outcompetes the antitumorigenic CD8+ T cells while promoting the protumorigenic exhausted CD8+ T cells and T regulatory (Treg) cells. Thus, cancer cells elude the immune response and spread in an uncontrolled manner. Identifying the metabolic pathways necessary to shift the balance from a protumorigenic to an antitumorigenic immune phenotype is essential to potentiate antitumor immunity.

Keywords: antitumorigenic T cells; immunometabolism; protumorigenic T cells; tumor microenvironment

DOI: https://doi.org/10.1016/j.tibs.2023.03.004

J Nutr. 2023 Apr;pii: S0022-3166(22)13243-8. [Epub ahead of print]153(4): 988-998

Glucose-Induced Activation of mTORC1 is Associated with Hexokinase2 Binding to Sestrins in HEK293T Cells.

Paul A Roberson, Gregory N Kincheloe, Jaclyn E Welles, Dandan Xu, Mahalia Sam-Clarke, Paul S MacLean, Charles H Lang, Leonard S Jefferson, Scot R Kimball.

BACKGROUND: Sestrins (SESN1-3) act as proximal sensors in leucine-induced activation of the protein kinase mechanistic target of rapamycin (mTOR) in complex 1 (mTORC1), a key regulator of cell growth and metabolism.
OBJECTIVE: In the present study, the hypothesis that SESNs also mediate glucose-induced activation of mTORC1 was tested.
METHODS: Rats underwent overnight fasting, and in the morning, either saline or a glucose solution (4 g⋅kg-1 BW/10 mL⋅kg-1) was administered by oral gavage; mTORC1 activation in the tibialis anterior muscle was assessed. To further assess the mechanism through which glucose promotes mTORC1 activation, wild-type (WT) HEK293T and HEK293T cells lacking either all 3 SESNs (SESNTKO) or hexokinase 2 (HK2KO) were deprived of glucose, followed by glucose addback, and mTORC1 activation was assessed. In addition, glucose-induced changes in the association of the SESNs with components of the GAP activity toward the Rags (GATOR2) complex and with hexokinase 2 (HK2) were assessed by co-immunoprecipitation. One- and two-way ANOVA with Tukey post hoc comparisons were used.
RESULTS: Glucose administration to fasted rats promoted mTORC1 activation. Similarly, glucose readdition (GluAB) to the medium of glucose-deprived WT cells also promoted mTORC1 activation. By contrast, SESNTKO cells demonstrated attenuated mTORC1 activation following GluAB compared with WT cells. Interestingly, HK2 associated with all 3 SESNs in a glucose-dependent manner, i.e., HK2 abundance in SESN immunoprecipitates was high in cells deprived of glucose and decreased in response to GluAB. Moreover, similar to SESNTKO cells, the sensitivity of mTORC1 to GluAB was attenuated in HK2KO cells compared with WT cells.
CONCLUSIONS: The results of this study demonstrate that the SESNs and HK2 play important roles in glucose-induced mTORC1 activation in HEK293T cells. However, unlike leucine-induced mTORC1 activation, the effect was independent of the changes in SESN-GATOR2 interaction, and instead, it was associated with alterations in the association of SESNs with HK2.

Keywords: glucose; mTORC1; metabolism; nutrient signaling; skeletal muscle

DOI: https://doi.org/10.1016/j.tjnut.2022.11.021