Parallel phosphoproteomics and metabolomics map the global metabolic tyrosine phosphoproteome.

Tyrosine phosphorylation of metabolic enzymes is an evolutionarily conserved posttranslational modification that facilitates rapid and reversible modulation of enzyme activity, localization, or function. Despite the high abundance of tyrosine phosphorylation events detected on metabolic enzymes in high-throughput mass spectrometry-based studies, functional characterization of tyrosine phosphorylation sites has been limited to a subset of enzymes. Since tyrosine phosphorylation is dysregulated across human diseases, including cancer, understanding the consequences of metabolic enzyme tyrosine phosphorylation events is critical for informing disease biology and therapeutic interventions.

Phosphoproteomics-directed manipulation reveals SEC22B as a hepatocellular signaling node governing metabolic actions of glucagon.

The peptide hormone glucagon is a fundamental metabolic regulator that is also being considered as a pharmacotherapeutic option for obesity and type 2 diabetes. Despite this, we know very little regarding how glucagon exerts its pleiotropic metabolic actions. Given that the liver is a chief site of action, we performed in situ time-resolved liver phosphoproteomics to reveal glucagon signaling nodes.

Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer.

To delineate the mechanisms by which the ERK1 and ERK2 mitogen-activated protein kinases support mutant KRAS-driven cancer growth, we determined the ERK-dependent phosphoproteome in KRAS-mutant pancreatic cancer. We determined that ERK1 and ERK2 share near-identical signaling and transforming outputs and that the KRAS-regulated phosphoproteome is driven nearly completely by ERK. We identified 4666 ERK-dependent phosphosites on 2123 proteins, of which 79 and 66%, respectively, were not previously associated with ERK, substantially expanding the depth and breadth of ERK-dependent phosphorylation events and revealing a considerably more complex function for ERK in cancer.

A Flexible Mouse Model of Autoimmune Thyroiditis Induced by Immunization with an Adenovirus Containing Full-Length Thyroglobulin cDNA.

The main challenge in the "post-GWAS" era is to determine the functional meaning of genetic variants and their contribution to disease pathogenesis. Development of suitable mouse models is critical because disease susceptibility is triggered by complex interactions between genetic, epigenetic, and environmental factors that cannot be modeled by in vitro models. Thyroglobulin (TG) is a key gene for autoimmune thyroid disease (AITD) and several single nucleotide polymorphisms (SNPs) in the TG coding region have been associated with AITD.

Epinephrine inhibits PI3Kα via the Hippo kinases.

The phosphoinositide 3-kinase p110α is an essential mediator of insulin signaling and glucose homeostasis. We interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110α and found that the Hippo kinases phosphorylate p110α at T1061, which inhibits its activity. This inhibitory state corresponds to a conformational change of a membrane-binding domain on p110α, which impairs its ability to engage membranes.

Pan-cancer proteogenomics connects oncogenic drivers to functional states.

Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis uncovers insights into the impacts of cancer drivers by identifying their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles.

SARS-CoV-2 hijacks p38β/MAPK11 to promote virus replication.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, drastically modifies infected cells to optimize virus replication. One such modification is the activation of the host p38 mitogen-activated protein kinase (MAPK) pathway, which plays a major role in inflammatory cytokine production, a hallmark of severe COVID-19. We previously demonstrated that inhibition of p38/MAPK activity in SARS-CoV-2-infected cells reduced both cytokine production and viral replication.

Perturbation of endoplasmic reticulum proteostasis triggers tissue injury in the thyroid gland.

Defects in endoplasmic reticulum (ER) proteostasis have been linked to diseases in multiple organ systems. Here we examined the impact of perturbation of ER proteostasis in mice bearing thyrocyte-specific knockout of either HRD1 (to disable ER-associated protein degradation [ERAD]) or ATG7 (to disable autophagy) in the absence or presence of heterozygous expression of misfolded mutant thyroglobulin (the most highly expressed thyroid gene product, synthesized in the ER). Misfolding-inducing thyroglobulin mutations are common in humans but are said to yield only autosomal-recessive disease - perhaps because misfolded thyroglobulin protein might undergo disposal by ERAD or ER macroautophagy.

Permanent hypothyroidism following immune checkpoint inhibitors induced thyroiditis may be associated with improved survival: results of an exploratory study.

Background: Immune-related endocrinopathies are common after immune checkpoint inhibitor (ICI) therapy, among which destructive thyroiditis is the most prevalent. Improved survival outcomes have been associated with immune-related adverse events. We aimed to compare the clinical course and biochemical parameters of two subtypes of ICI-related destructive thyroiditis: a transient thyrotoxicosis that reverts to either euthyroidism (TT; transient thyroiditis) versus progression to permanent hypothyroidism (PH), and to identify prognostic markers in cancer patients receiving ICI therapy who developed DT.

RBFOX2 modulates a metastatic signature of alternative splicing in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) is characterized by aggressive local invasion and metastatic spread, leading to high lethality. Although driver gene mutations during PDA progression are conserved, no specific mutation is correlated with the dissemination of metastases. Here we analysed RNA splicing data of a large cohort of primary and metastatic PDA tumours to identify differentially spliced events that correlate with PDA progression.

Effective Inhibition of Thyroid Antigen Presentation Using Retro-Inverso Peptides in Experimental Autoimmune Thyroiditis: A Pathway Toward Immune Therapies of Thyroid Autoimmunity.

Autoimmune thyroid diseases (AITD) represent the most common autoimmune diseases. However, current therapies focus on relieving the symptoms instead of curing AITD, and new therapies to reverse the autoimmune attack on the thyroid are needed. HLA-DRβ1-Arg74 is the key HLA class II allele that triggers AITD by presenting pathogenic thyroglobulin (Tg) peptides that activate thyroid self-reactive T cells.

Host protein kinases required for SARS-CoV-2 nucleocapsid phosphorylation and viral replication.

Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets.

In-Hospital Hyperglycemia Is Associated With Worse Outcomes in Patients Admitted With COVID-19.

Objective: Diabetes and the outpatient diabetes treatment regimen have been identified as risk factors for poor outcomes in patients with sepsis. However, little is known about the effect of tight inpatient glycemic control in the setting of coronavirus disease 2019 (COVID-19). Therefore, we examined the effect of hyperglycemia in patients with diabetes hospitalized because of COVID-19.

Evolution of host protease interactions among SARS-CoV-2 variants of concern and related coronaviruses.

Previously, we showed that coagulation factors directly cleave SARS-CoV-2 spike and promote viral entry (Kastenhuber et al., 2022). Here, we show that substitutions in the S1/S2 cleavage site observed in SARS-CoV-2 variants of concern (VOCs) exhibit divergent interactions with host proteases, including factor Xa and furin.

Physician Electronic Health Record Usage as Affected by the COVID-19 Pandemic.

Objectives: To utilize metrics from physician action logs to analyze volume, physician efficiency and burden as impacted by telemedicine implementation during the COVID-19 (coronavirus disease 2019) pandemic, and physician characteristics such as gender, years since graduation, and specialty category.

Methods: We selected 11 metrics from Epic Signal, a functionality of the Epic electronic health record (EHR). Metrics measuring time spent in the EHR outside working hours were used as a correlate for burden.

Genetics and epigenetics of autoimmune thyroid diseases: Translational implications.

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are prevalent autoimmune disorders, representing opposite ends of the clinical spectrum of autoimmune thyroid diseases (AITD). The pathogenesis involves a complex interplay between environment and genes. Specific susceptibility genes have been discovered that predispose to AITD, including thyroid-specific and immune-regulatory genes.

Cepharanthine Blocks Presentation of Thyroid and Islet Peptides in a Novel Humanized Autoimmune Diabetes and Thyroiditis Mouse Model.

Autoimmune polyglandular syndrome type 3 variant (APS3v) refers to an autoimmune condition in which both type 1 diabetes (T1D) and autoimmune thyroiditis (AITD) develop in the same individual. HLA-DR3 confers the strongest susceptibility to APS3v. Previously we reported a unique amino acid signature pocket that predisposes to APS3v.

Hyperglycemic Emergencies Associated With COVID-19 Vaccination: A Case Series and Discussion.

Context: Hyperglycemic emergencies such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome (HHS) and new-onset diabetes mellitus (DM) have been reported in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Hyperglycemia is a predictor of poor prognosis in COVID-19 disease.

Objectives: The objective of this work is to describe a case series of HHS and/or DKA likely triggered by the COVID-19 vaccine.

Precision Medicine in Graves' Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody.

Background: CD40, a key co-stimulatory molecule expressed on antigen-presenting cells, is genetically associated with a number of autoimmune diseases including Graves' disease (GD). Therefore, recent therapies targeting CD40 have been developed, including the anti-CD40 monoclonal antibody Iscalimab. In a recent pilot study, Iscalimab was shown to induce clinical remission in ~ 50% of GD patients, but the reason why only 50% of GD patients responded is not known.