Biology subjects

Dejgaard, K.

Publications and source records attributed to Dejgaard, K..

3 recordsLinked to original sources

bioRxiv2024

Proximity Interactome analyses unveil novel regulators of IRE1a canonical signaling

The unfolded protein response (UPR) is a key adaptive pathway that controls endoplasmic reticulum (ER) homeostasis. The UPR is transduced by three ER-resident sensors of ER homeostasis disruption in the lumen of this compartment. They trigger select downstream signaling pathways in the cytosol and nucleus. Among them, IRE1 (referred to as IRE1 hereafter), a type I transmembrane protein, senses accumulation of improperly folded proteins in the ER lumen and transduces signals through both kinase and endoribonuclease (RNase) activities in the cytosol. IRE1 catalyzes XBP1 mRNA unconventional splicing and RNA degradation (Regulated IRE1 Dependent Decay, termed RIDD). Recent studies have reported that IRE1-dependent protein-protein interactions (PPi) drive additional non-canonical IRE1 functions. Herein, we define the IRE1 signalosome as a list of IRE1 binding partners (direct or not) which alter IRE1 signaling towards XBP1 mRNA splicing and RIDD. Here we determined the IRE1 in situ interactome using BioID, putatively connecting IRE1 to previously unrecognized cellular functions. In addition, we link the binding of several IRE1 partners to the regulation of its RNase. Furthermore, we identify HNRNPL as an IRE1-interacting partner, previously unrecognized, which stabilizes IRE1 under basal conditions by counteracting ERAD-mediated degradation. Overall, the characterization of the IRE1 signalosome not only reveals the multi-faceted control of IRE1 RNase activity and stability by its interacting partners and allow us to discuss putative additional IRE1 regulators and cellular functions based on the nature of its interactome and its localization.

biochemistry↗

bioRxiv2023

Molecular signatures of hyperexcitability and lithium responsiveness in bipolar disorder patient neurons provide alternative therapeutic strategies.

Bipolar disorder (BD) is a multifactorial psychiatric illness affecting about 1% of the world population. The first line treatment, lithium (Li), is effective in only a subset of patients and its mechanism of action remains largely elusive. In the present study, we used iPSC-derived neurons from BD patients responsive (LR) or not (LNR) to lithium and combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics to report mechanistic insights into neuronal hyperactivity in BD, and Lis mode of action. We show a selective rescue of neuronal hyperactivity by Li in BD LR neurons through changes in Na+ currents. The whole transcriptome sequencing revealed altered gene expression in BD neurons in pathways related to glutamatergic transmission, and Li selectively altered those involved in cell signaling and ion transport/channel activity. We found the therapeutic effect of Li in BD LR patients was associated with Akt signaling and confirmed that an Akt activator mimics Li effect in BD LR neurons. Further, we showed that AMP-activated protein kinase (AMPK) reduces neural network activity and sodium currents in BD LNR patients. These findings suggest the potential for novel treatment strategies in BD, such as Akt activators in BD LR cases, and the use of AMPK activators for BD LNR patients.

neuroscience↗

bioRxiv2021

AMPK-dependent phosphorylation is required for transcriptional activation of TFEB/TFE3

Increased autophagy and lysosomal activity promote tumor growth, survival and chemo-resistance. During acute starvation, autophagy is rapidly engaged by AMPK activation and mTORC1 inhibition to maintain energy homeostasis and cell survival. TFEB and TFE3 are master transcriptional regulators of autophagy and lysosomal activity and their cytoplasm/nuclear shuttling is controlled by mTORC1-dependent multisite phosphorylation. However, it is not known whether and how the transcriptional activity of TFEB or TFE3 is regulated. We show that AMPK mediates phosphorylation of TFEB and TFE3 on three serine residues, leading to TFEB/TFE3 transcriptional activity upon nutrient starvation, FLCN depletion and pharmacological manipulation of mTORC1 or AMPK. AMPK loss does not affect TFEB/TFE3 nuclear localization nor protein levels but reduces their transcriptional activity. Collectively, we show that mTORC1 specifically controls TFEB/TFE3 cytosolic retention whereas AMPK is essential for TFEB/TFE3 transcriptional activity. This dual and opposing regulation of TFEB/TFE3 by mTORC1 and AMPK is reminiscent of the regulation of another critical regulator of autophagy, ULK1. Surprisingly, we show that chemoresistance is mediated by AMPK-dependent activation of TFEB, which is abolished by pharmacological inhibition of AMPK or mutation of serine 466/467/469 to alanine residues within TFEB. Altogether, we show that AMPK is a key regulator of TFEB/TFE3 transcriptional activity, and we validate AMPK as a promising target in cancer therapy to evade chemotherapeutic resistance.

cancer biology↗