Publications by authors named "Anthony J Domma"

The surfaces of cells and enveloped viruses alike are coated in carbohydrates that play multifarious roles in infection and immunity. Organisms across all kingdoms of life make use of a diverse set of monosaccharide subunits, glycosidic linkages, and branching patterns to encode information within glycans. Accordingly, sugar-patterning enzymes and glycan binding proteins play integral roles in cell and organismal biology, ranging from glycoprotein quality control within the endoplasmic reticulum to lymphocyte migration, coagulation, inflammation, and tissue homeostasis.

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Human cytomegalovirus (HCMV) requires inactivation of AKT to efficiently replicate, yet how AKT is shut off during HCMV infection has remained unclear. We show that UL38, an HCMV protein that activates mTORC1, is necessary and sufficient to destabilize insulin receptor substrate 1 (IRS1), a model insulin receptor substrate (IRS) protein. Degradation of IRS proteins in settings of excessive mTORC1 activity is an important mechanism for insulin resistance.

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Article Synopsis
  • The PI3K/AKT pathway is vital for cell survival and protein synthesis, but some viruses, including HCMV, can manipulate it to their advantage, leading to AKT's inactivation during infection.
  • HCMV requires FoxO transcription factors to enter the cell nucleus, which is hindered by active AKT; the study showed that viral gene expression is necessary to keep AKT from responding to growth signals like serum.
  • The viral protein UL38 plays a key role in reducing AKT activity by promoting the degradation of IRS1, a protein essential for AKT activation, and this process can be inhibited by the mTORC1 inhibitor rapamycin.
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Article Synopsis
  • - The protein kinase Akt plays a crucial role in various cellular processes, and its inhibition can trigger herpesviruses to reactivate from latency, indicating that decreased Akt activity might encourage lytic replication.
  • - During human cytomegalovirus (HCMV) infection, Akt is found in an inactive state within fibroblasts, linked to specific changes in phosphorylation patterns and the localization of the substrate FoxO3a, while mTORC1 activation further contributes to Akt inactivation.
  • - Unexpectedly, maintaining active Akt (myr-Akt) reduces viral replication, revealing that the inactivation of Akt is necessary for efficient HCMV replication, primarily through the involvement of FoxO3a.
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The human cytomegalovirus (HCMV) endoplasmic reticulum (ER)-resident glycoprotein UL148 is posited to play roles in immune evasion and regulation of viral cell tropism. UL148 prevents cell surface presentation of the immune cell costimulatory ligand CD58 while promoting maturation and virion incorporation of glycoprotein O, a receptor binding subunit for an envelope glycoprotein complex involved in entry. Meanwhile, UL148 activates the unfolded protein response (UPR) and causes large-scale reorganization of the ER.

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Eukaryotic cells are equipped with three sensors that respond to the accumulation of misfolded proteins within the lumen of the endoplasmic reticulum (ER) by activating the unfolded protein response (UPR), which functions to resolve proteotoxic stresses involving the secretory pathway. Here, we identify UL148, a viral ER-resident glycoprotein from human cytomegalovirus (HCMV), as an inducer of the UPR. Metabolic labeling results indicate that global mRNA translation is decreased when UL148 expression is induced in uninfected cells.

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