L. Wiseman

Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations

The paper identifies the integrated stress response (ISR) as the primary signaling pathway activated by mitochondrial proteostasis stress using gene set profiling in Perturb-seq datasets.

Adaptive IRE1 Signaling Elicits T Cell Metabolic Remodeling and Tumor Control

This study shows that enhancing the adaptive IRE1 UPR pathway in T cells improves tumor control by reducing mitochondrial toxicity and chronic ER stress.

Pharmacologic Targeting of PDIA1 Inhibits NLRP3 Inflammasome Assembly and Activation

This study shows that AA147 inhibits NLRP3 inflammasome activity by covalently modifying PDIA1, suggesting PDIA1 as a therapeutic target for inflammatory diseases.

Covalent targeting as a common mechanism for inhibiting NLRP3 inflammasome assembly.

This study identifies covalent compounds that inhibit NLRP3 inflammasome assembly by targeting reactive cysteines, suggesting NLRP3 as an electrophile sensor for inflammatory signaling.

Succinylation of a KEAP1 sensor lysine promotes NRF2 activation

The paper identifies succinylation of KEAP1 lysine 131 as a mechanism to activate NRF2 transcriptional signaling through metabolic regulation.

Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells

This study shows that halofuginone can compensate for PERK signaling deficiencies by promoting adaptive mitochondrial remodeling, while BtdCPU causes mitochondrial fragmentation.

Divergent Proteome Reactivity Influences Arm-Selective Activation of Pharmacological Endoplasmic Reticulum Proteostasis Regulators

This study shows that AA132, a compound with a 2-amino-p-cresol substructure, globally activates all three UPR arms by covalently modifying ER PDIs, while AA147 selectively activates the ATF6 arm.

Imbalanced Unfolded Protein Response Signaling Contributes to 1-Deoxysphingolipid Retinal Toxicity

This study identifies imbalanced UPR signaling as a mechanism of 1-dSL-induced retinal toxicity and suggests therapeutic targets.

ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion Through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors

This study identifies how ATF6 activation reduces amyloidogenic TTR secretion through ER retention mediated by BiP and PDIA4, independent of redox activity.

Circadian disruption enhances HSF1 signaling and tumorigenesis in Kras-driven lung cancer

This study shows that chronic circadian disruption increases tumor burden in KRAS-driven lung cancer by enhancing HSF1 signaling and tumorigenesis.

Metabolically Activated Proteostasis Regulators Protect Against Glutamate Toxicity by Activating NRF2

The paper shows AA147 protects neurons from glutamate toxicity by activating NRF2, highlighting its potential as a therapeutic for neurodegenerative diseases.

Pharmacologic IRE1/XBP1s Activation Promotes Systemic Adaptive Remodeling in Obesity

This study shows that pharmacologic activation of IRE1/XBP1s signaling in obese mice improves glucose metabolism, insulin action, and reduces hepatic steatosis and inflammation.

ER Proteostasis Regulators Reduce Amyloidogenic Light Chain Secretion Through an On-Target, ATF6-Independent Mechanism

This paper shows that compound 147 reduces amyloidogenic light chain secretion from AL patient plasma cells through PDI modification, independent of ATF6 activation.