Vps34 and TOR Kinases Coordinate <i>HAC1</i> mRNA Translation in the Presence or Absence of Ire1-Dependent Splicing

Uppala, Jagadeesh Kumar; Bhattacharjee, Sankhajit; Dey, Madhusudan

doi:10.1128/mcb.00662-20

Cited by 6 publications

(4 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, cell-autonomous responses involving PERK triggering by STING have been shown to regulate translation of viral and host proteins ( 53 ), as well as to protect cell integrity from the co-lateral damages linked to STING activation ( 54,55 , 56 ). In regards to the protein synthesis inhibition observed upon VPS34-IN1 treatment, we investigated the capacity of the drug to trigger an ER stress unfolded protein response (UPR) by altering the lipid composition and dynamics of ER membranes targeted by the PI3KC3-CI complex ( 57 ) (Fig. EV1D).…”

Section: Resultsmentioning

confidence: 99%

VPS34-IN1 inhibits cap-mediated translation and synergizes with STING to drive type-I IFN expression in human plasmacytoid DCs

Antas,

Machado,

Leite-Pinheiro

et al. 2024

Preprint

View full text Add to dashboard Cite

Inhibition of the phosphatidylinositol kinase vacuolar protein sorting 34 (VPS34) with the pharmacological compound VPS34-IN1 has a range of effects on the dynamics of endosomes. While VPS34 inhibition has been suggested as a potential therapeutic approach for treating certain cancers, our findings indicate that it has minimal cytotoxic effects on leukemic blastic plasmacytoid dendritic cell neoplasms (BPDCN). VPS34-IN1, however, interferes with plasmacytoid dendritic cells (pDCs) function by blocking the recruitment of serum and glucocorticoid-regulated kinase 3 (SGK3) to endosomes, which is shown to be necessary for Toll-like receptor 7 (TLR7) signaling. In a contrasting parallel, VPS34-IN1 triggers the activation of the stimulator of interferon genes (STING) and significantly enhances pDCs’ response to the STING agonist 2’3’-cyclic guanosine monophosphate-adenosine monophosphate (2’3’-cGAMP). This cooperative action with VPS34-IN1 leads to strongly increased expression of type-I interferons (IFNs), associated with an alteration of STING degradation and importantly, inhibition of cap-mediated mRNA translation. Inhibition of protein synthesis by VPS34-IN1 appears to be central to this synergy with STING activation, notably by compromising the expression of IFIT1/ISG56, a negative regulator of innate signaling. Thus, despite their limited toxicity towards different cancer lines, inhibitors targeting VPS34 and SGK3 may present promising compounds for controlling the expression of type-I IFNs in response to various microbial stimuli and pathological contexts.One-sentence summaryPharmacological inhibition of VPS34 affects multiple signaling pathways downstream of innate immunity receptors and consequently can inhibit or potentiate type-I Interferon induction according to the danger or microbial stimuli received by plasmacytoid DCs.

show abstract

Section: Resultsmentioning

confidence: 99%

VPS34-IN1 inhibits cap-mediated translation and synergizes with STING to drive type-I IFN expression in human plasmacytoid DCs

Antas,

Machado,

Leite-Pinheiro

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…However, this method is indirect and may result in occasional biases. If HAC1i mRNA is poorly translated, Hac1-target gene expression is low, even in ER-stressed cells in which Ire1 is highly activated [12]. In contrast, expression of the most prominent Hac1-target gene, KAR2, is also upregulated by heat shock independently of UPR [13], though KAR2 expression is frequently regarded as an indicator for cellular ER-stress and UPR levels.…”

Section: Discussionmentioning

confidence: 99%

Induction of the Unfolded Protein Response at High Temperature in Saccharomyces cerevisiae

Hata

Ishiwata-Kimata

2022

IJMS

View full text Add to dashboard Cite

Ire1 is an endoplasmic reticulum (ER)-located endoribonuclease that is activated in response to ER stress. In yeast Saccharomyces cerevisiae cells, Ire1 promotes HAC1-mRNA splicing to remove the intron sequence from the HAC1u mRNA (“u” stands for “uninduced”). The resulting mRNA, which is named HAC1i mRNA (“i” stands for “induced”), is then translated into a transcription factor that is involved in the unfolded protein response (UPR). In this study, we designed an oligonucleotide primer that specifically hybridizes to the exon-joint site of the HAC1i cDNA. This primer allowed us to perform real-time reverse transcription-PCR to quantify HAC1i mRNA abundance with high sensitivity. Using this method, we detected a minor induction of HAC1-mRNA splicing in yeast cells cultured at their maximum growth temperature of 39 °C. Based on our analyses of IRE1-gene mutant strains, we propose that when yeast cells are cultured at or near their maximum growth temperature, protein folding in the ER is disturbed, leading to a minor UPR induction that supports cellular growth.

show abstract

“…According to Sarkar et al [46], HAC1u mRNA is rapidly digested under non-stress conditions. In addition, Uppala et al [47] proposed a role of certain signaling pathways that repress HAC1 mRNA translation independent of its splicing.…”

Section: Upr Inducing and Repressing Mechanisms In S Cerevisiae Cellsmentioning

confidence: 99%

“…According to Halbleib et al [51], the transmembrane domain of Ire1 takes a unique form that is responsible for the self-association of Ire1 in response to LBS (Figure 3). addition, Uppala et al [47] proposed a role of certain signaling pathways that repress HAC1 mRNA translation independent of its splicing. Taken together, the UPR level is tightly controlled to avoid an inappropriate UPR under no or weak stress conditions.…”

Section: Scenes In Which the Upr Is Provoked In S Cerevisiae Cellsmentioning

confidence: 99%

Fundamental and Applicative Aspects of the Unfolded Protein Response in Yeasts

Ishiwata-Kimata,

Kimata

2023

JoF

View full text Add to dashboard Cite

Upon the dysfunction or functional shortage of the endoplasmic reticulum (ER), namely, ER stress, eukaryotic cells commonly provoke a protective gene expression program called the unfolded protein response (UPR). The molecular mechanism of UPR has been uncovered through frontier genetic studies using Saccharomyces cerevisiae as a model organism. Ire1 is an ER-located transmembrane protein that directly senses ER stress and is activated as an RNase. During ER stress, Ire1 promotes the splicing of HAC1 mRNA, which is then translated into a transcription factor that induces the expression of various genes, including those encoding ER-located molecular chaperones and protein modification enzymes. While this mainstream intracellular UPR signaling pathway was elucidated in the 1990s, new intriguing insights have been gained up to now. For instance, various additional factors allow UPR evocation strictly in response to ER stress. The UPR machineries in other yeasts and fungi, including pathogenic species, are another important research topic. Moreover, industrially beneficial yeast strains carrying an enforced and enlarged ER have been produced through the artificial and constitutive induction of the UPR. In this article, we review canonical and up-to-date insights concerning the yeast UPR, mainly from the viewpoint of the functions and regulation of Ire1 and HAC1.

show abstract

Vps34 and TOR Kinases Coordinate HAC1 mRNA Translation in the Presence or Absence of Ire1-Dependent Splicing

Cited by 6 publications

References 67 publications

VPS34-IN1 inhibits cap-mediated translation and synergizes with STING to drive type-I IFN expression in human plasmacytoid DCs

VPS34-IN1 inhibits cap-mediated translation and synergizes with STING to drive type-I IFN expression in human plasmacytoid DCs

Induction of the Unfolded Protein Response at High Temperature in Saccharomyces cerevisiae

Fundamental and Applicative Aspects of the Unfolded Protein Response in Yeasts

Contact Info

Product

Resources

About