Dataset Information

Phosphorylation-Mediated Clearance of Amyloid-like Assemblies in Meiosis.

ABSTRACT: Amyloids are fibrous protein assemblies that are often described as irreversible and intrinsically pathogenic. However, yeast cells employ amyloid-like assemblies of the RNA-binding protein Rim4 to control translation during meiosis. Here, we show that multi-site phosphorylation of Rim4 is critical for its regulated disassembly and degradation and that failure to clear Rim4 assemblies interferes with meiotic progression. Furthermore, we identify the protein kinase Ime2 to bring about Rim4 clearance via phosphorylation of Rim4's intrinsically disordered region. Rim4 phosphorylation leads to reversal of its amyloid-like properties and degradation by the proteasome. Our data support a model in which a threshold amount of phosphorylation, rather than modification of critical residues, is required for Rim4 clearance. Our results further demonstrate that at least some amyloid-like assemblies are not as irreversible as previously thought. We propose that the natural pathways by which cells process these structures could be deployed to act on disease-related amyloids.

SUBMITTER: Carpenter K

PROVIDER: S-EPMC5944619 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Phosphorylation-Mediated Clearance of Amyloid-like Assemblies in Meiosis.

Carpenter Kayla K Bell Rachel Brietta RB Yunus Julius J Amon Angelika A Berchowitz Luke Edwin LE

Developmental cell 20180501 3

Amyloids are fibrous protein assemblies that are often described as irreversible and intrinsically pathogenic. However, yeast cells employ amyloid-like assemblies of the RNA-binding protein Rim4 to control translation during meiosis. Here, we show that multi-site phosphorylation of Rim4 is critical for its regulated disassembly and degradation and that failure to clear Rim4 assemblies interferes with meiotic progression. Furthermore, we identify the protein kinase Ime2 to bring about Rim4 cleara ...[more]

PMID: 29738715

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Project description:Osteopontin (OPN), a matricellular immunomodulatory cytokine highly expressed by myelomonocytic cells, is known to regulate immune cell migration, communication, and response to brain injury. Enhanced cerebral recruitment of monocytes achieved through glatiramer acetate (GA) immunization or peripheral blood enrichment with bone marrow (BM)-derived CD115+ monocytes (MoBM) curbs amyloid β-protein (Aβ) neuropathology and preserves cognitive function in murine models of Alzheimer's disease (ADtg mice). To elucidate the beneficial mechanisms of these immunomodulatory approaches in AD, we focused on the potential role of OPN in macrophage-mediated Aβ clearance. Here, we found extensive OPN upregulation along with reduction of vascular and parenchymal Aβ burden in cortices and hippocampi of GA-immunized ADtg mice. Treatment combining GA with blood-grafted MoBM further increased OPN levels surrounding residual Aβ plaques. In brains from AD patients and ADtg mice, OPN was also elevated and predominantly expressed by infiltrating GFP+- or Iba1+-CD45high monocyte-derived macrophages engulfing Aβ plaques. Following GA immunization, we detected a significant increase in a subpopulation of inflammatory blood monocytes (CD115+CD11b+Ly6Chigh) expressing OPN, and subsequently, an elevated population of OPN-expressing CD11b+Ly6C+CD45high monocyte/macrophages in the brains of these ADtg mice. Correlogram analyses indicate a strong linear correlation between cerebral OPN levels and macrophage infiltration, as well as a tight inverse relation between OPN and Aβ-plaque burden. In vitro studies corroborate in vivo findings by showing that GA directly upregulates OPN expression in BM-derived macrophages (MФBM). Further, OPN promotes a phenotypic shift that is highly phagocytic (increased uptake of Aβ fibrils and surface scavenger receptors) and anti-inflammatory (altered cell morphology, reduced iNOS, and elevated IL-10 and Aβ-degrading enzyme MMP-9). Inhibition of OPN expression in MФBM, either by siRNA, knockout (KOOPN), or minocycline, impairs uptake of Aβ fibrils and hinders GA's neuroprotective effects on macrophage immunological profile. Addition of human recombinant OPN reverses the impaired Aβ phagocytosis in KOOPN-MФBM. This study demonstrates that OPN has an essential role in modulating macrophage immunological profile and their ability to resist pathogenic forms of Aβ.

Dataset Information

Phosphorylation-Mediated Clearance of Amyloid-like Assemblies in Meiosis.

Publications

Phosphorylation-Mediated Clearance of Amyloid-like Assemblies in Meiosis.

Similar Datasets

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