18 research outputs found
A Single Residue Exchange Within a Viral CTL Epitope Alters Proteasome-Mediated Degradation Resulting in Lack of Antigen Presentation
AbstractCTL epitope (KSPWFTTL) encoded by AKV/MCF type of murine leukemia virus (MuLV) differs from the sequence in Friend/Moloney/Rauscher (FMR) type in one residue (RSPWFTTL). CTL experiments indicated defective processing of the FMR peptide in tumor cells. Proteasome-mediated digestion of AKV/MCF-type 26-mer peptides resulted in the early generation and higher levels of epitope-containing fragments than digestion of FMR-type peptides, explained by prominent cleavage next to R in the FMR sequence. The fragments were identified as 10- and 11-mer peptides and were efficiently translocated by TAP. The naturally presented AKV/MCF peptide is the 8-mer, indicating ER peptide trimming. In conclusion, a single residue exchange can cause CTL epitope destruction by specific proteasomal cleavage
APOE3, but Not APOE4, Bone Marrow Transplantation Mitigates Behavioral and Pathological Changes in a Mouse Model of Alzheimer Disease
Apolipoprotein E4 (APOE4) genotype is the strongest genetic risk factor for late-onset Alzheimer disease and confers a proinflammatory, neurotoxic phenotype to microglia. Here, we tested the hypothesis that bone marrow cell APOE genotype modulates pathological progression in experimental Alzheimer disease. We performed bone marrow transplants (BMT) from green fluorescent proteinâexpressing human APOE3/3 or APOE4/4 donor mice into lethally irradiated 5-month-old APPswe/PS1ÎE9 mice. Eight months later, APOE4/4 BMTârecipient APPswe/PS1ÎE9 mice had significantly impaired spatial working memory and increased detergent-soluble and plaque AÎČ compared with APOE3/3 BMTârecipient APPswe/PS1ÎE9 mice. BMT-derived microglia engraftment was significantly reduced in APOE4/4 recipients, who also had correspondingly less cerebral apoE. Gene expression analysis in cerebral cortex of APOE3/3 BMT recipients showed reduced expression of tumor necrosis factor-α and macrophage migration inhibitory factor (both neurotoxic cytokines) and elevated immunomodulatory IL-10 expression in APOE3/3 recipients compared with those that received APOE4/4 bone marrow. This was not due to detectable APOE-specific differences in expression of microglial major histocompatibility complex class II, C-C chemokine receptor (CCR) type 1, CCR2, CX3C chemokine receptor 1 (CX3CR1), or C5a anaphylatoxin chemotactic receptor (C5aR). Together, these findings suggest that BMT-derived APOE3-expressing cells are superior to those that express APOE4 in their ability to mitigate the behavioral and neuropathological changes in experimental Alzheimer disease
Mu opioid receptor stimulation activates c-Jun N-terminal kinase 2 by distinct arrestin-dependent and independent mechanisms
G protein-coupled receptor desensitization is typically mediated by receptor phosphorylation by G proteincoupled
receptor kinase (GRK) and subsequent arrestin binding; morphine, however, was previously found to
activate a c-Jun N-terminal kinase (JNK)-dependent, GRK/arrestin-independent pathway to produce mu opioid
receptor (MOR) inactivation in spinally-mediated, acute anti-nociceptive responses [Melief et al.] [1]. In the current
study, we determined that JNK2 was also required for centrally-mediated analgesic tolerance to morphine
using the hotplate assay. We compared JNK activation by morphine and fentanyl in JNK1â/â, JNK2â/â, JNK3â/â,
and GRK3â/âmice and found that both compounds specifically activate JNK2 in vivo; however, fentanyl activation
of JNK2 was GRK3-dependent, whereasmorphine activation of JNK2 was GRK3-independent. InMOR-GFP expressing
HEK293 cells, treatment with either arrestin siRNA, the Src family kinase inhibitor PP2, or the protein kinase C
(PKC) inhibitor Gö6976 indicated that morphine activated JNK2 through an arrestin-independent Src- and PKCdependent
mechanism, whereas fentanyl activated JNK2 through a Src-GRK3/arrestin-2-dependent and PKCindependent
mechanism. This study resolves distinct ligand-directed mechanisms of JNK activation by mu opioid
agonists and understanding ligand-directed signaling at MOR may improve opioid therapeutic