Dysregulation of FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis.

Bi-functional enzyme FicD regulates the endoplasmic reticulum chaperone BiP using AMPylation and deAMPylation during ER homeostasis and stress, respectively. Human FicD with an arginine-to-serine mutation disrupts FicD deAMPylation activity resulting in severe neonatal diabetes. We generated the mutation in mice to create a pre-clinical murine model for neonatal diabetes.

FicD sensitizes cellular response to glucose fluctuations in mouse embryonic fibroblasts.

During homeostasis, the endoplasmic reticulum (ER) maintains productive transmembrane and secretory protein folding that is vital for proper cellular function. The ER-resident HSP70 chaperone, binding immunoglobulin protein (BiP), plays a pivotal role in sensing ER stress to activate the unfolded protein response (UPR). BiP function is regulated by the bifunctional enzyme filamentation induced by cyclic-AMP domain protein (FicD) that mediates AMPylation and deAMPylation of BiP in response to changes in ER stress.

FicD regulates adaptation to the unfolded protein response in the murine liver.

The unfolded protein response (UPR) is a cellular stress response that is activated when misfolded proteins accumulate in the endoplasmic reticulum (ER). Regulation of the UPR response must be adapted to the needs of the cell as prolonged UPR responses can result in disrupted cellular function and tissue damage. Previously, we discovered that the enzyme FicD (also known as Fic or HYPE) through its AMPylation and deAMPylation activity can modulate the UPR response via post-translational modification of BiP.

FicD regulates adaptation to the unfolded protein response in the murine liver.

The unfolded protein response (UPR) is a cellular stress response that is activated when misfolded proteins accumulate in the endoplasmic reticulum (ER). The UPR elicits a signaling cascade that results in an upregulation of protein folding machinery and cell survival signals. However, prolonged UPR responses can result in elevated cellular inflammation, damage, and even cell death.

FicD Sensitizes Cellular Response to Glucose Fluctuations in Mouse Embryonic Fibroblasts.

Unlabelled: During homeostasis, the endoplasmic reticulum (ER) maintains productive transmembrane and secretory protein folding that is vital for proper cellular function. The ER-resident HSP70 chaperone, BiP, plays a pivotal role in sensing ER stress to activate the unfolded protein response (UPR). BiP function is regulated by the bifunctional enzyme FicD that mediates AMPylation and deAMPylation of BiP in response to changes in ER stress.

Fic-mediated AMPylation tempers the unfolded protein response during physiological stress.

The proper balance of synthesis, folding, modification, and degradation of proteins, also known as protein homeostasis, is vital to cellular health and function. The unfolded protein response (UPR) is activated when the mechanisms maintaining protein homeostasis in the endoplasmic reticulum become overwhelmed. However, prolonged or strong UPR responses can result in elevated inflammation and cellular damage.

Role of Two Metacaspases in Development and Pathogenicity of the Rice Blast Fungus Magnaporthe oryzae.

Rice blast disease caused by is a devastating disease of cultivated rice worldwide. Infections by this fungus lead to a significant reduction in rice yields and threats to food security. To gain better insight into growth and cell death in during infection, we characterized two predicted metacaspase proteins, MoMca1 and MoMca2.

Proteomic Profiling of Small Extracellular Vesicles Secreted by Human Pancreatic Cancer Cells Implicated in Cellular Transformation.

Extracellular vesicles secreted from tumor cells are functional vehicles capable of contributing to intercellular communication and metastasis. A growing number of studies have focused on elucidating the role that tumor-derived extracellular vesicles play in spreading pancreatic cancer to other organs, due to the highly metastatic nature of the disease. We recently showed that small extracellular vesicles secreted from pancreatic cancer cells could initiate malignant transformation of healthy cells.

Human pancreatic cancer cell exosomes, but not human normal cell exosomes, act as an initiator in cell transformation.

Unlabelled: Cancer evolves through a multistep process that occurs by the temporal accumulation of genetic mutations. Tumor-derived exosomes are emerging contributors to tumorigenesis. To understand how exosomes might contribute to cell transformation, we utilized the classic two-step NIH/3T3 cell transformation assay and observed that exosomes isolated from pancreatic cancer cells, but not normal human cells, can initiate malignant cell transformation and these transformed cells formed tumors in vivo.

A calcium channel mutant mouse model of hypokalemic periodic paralysis.

Hypokalemic periodic paralysis (HypoPP) is a familial skeletal muscle disorder that presents with recurrent episodes of severe weakness lasting hours to days associated with reduced serum potassium (K+). HypoPP is genetically heterogeneous, with missense mutations of a calcium channel (Ca(V)1.1) or a sodium channel (Na(V)1.

A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis.

Hypokalemic periodic paralysis (HypoPP) is an ion channelopathy of skeletal muscle characterized by attacks of muscle weakness associated with low serum K+. HypoPP results from a transient failure of muscle fiber excitability. Mutations in the genes encoding a calcium channel (CaV1.

Systemic IFN-alpha drives kidney nephritis in B6.Sle123 mice.

The impact of IFN-alpha secretion on disease progression was assessed by comparing phenotypic changes in the lupus-prone B6.Sle1Sle2Sle3 (B6.Sle123) strain and the parental C57BL/6 (B6) congenic partner using an adenovirus (ADV) expression vector containing a recombinant IFN-alpha gene cassette (IFN-ADV).

Autoantibody profiling to identify individuals at risk for systemic lupus erythematosus.

The objective of this study was to determine the prevalence of lupus-related autoimmunity in a community-based cohort of over 3000 subjects, using a rheumatology registry as a comparison group. Measurements of ANA, anti-dsDNA and a panel of 8 other lupus-related autoantibodies were carried out in 176 subjects from the registry, including patients with SLE or with incomplete lupus (ILE) as well as in first degree relatives (FDRs) of these patients. Similar measurements were then carried out in 3470 samples from an unselected, urban community-based sample that included significant numbers of African-Americans and Hispanics.