English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Plus monthly

Global: Zendy Tools annual

Global: Zendy Tools monthly

Global: Zendy Free Plan

HLA (human leucocyte antigen)-A2 is an MHC Class I protein with primary functions in T-cell development and initi-ation of immune cell responses. MHC I proteins also play roles in intercellular adhesion, apoptosis, cell proliferation and neuronal plasticity. By utilizing a sequence comparison analysis, we recently identified HLA-A2 as a potential substrate for the Alzheimer's disease-associated PS1 (presenilin 1)/gamma-secretase. alpha-Secretase-like membrane metalloproteinases are responsible for an initial shedding event, partially mediated by ADAM (a disinteg-rin and metalloproteinase)-10. Accordingly, activation or inhibition of alpha-secretase-like membrane metalloproteinases directly modulated levels of a 14 kDa HLA-A2 CTF (C-terminal frag-ment) in CHO (Chinese-hamster ovary) cells. To show that the HLA-A2 CTF is subsequently cleaved by PS1/gamma-secretase, we re-duced its activity in cell lines stably expressing HLA-A2 and in Jurkat T-cells expressing endogenous MHC I. Treatment with specific PS1/gamma-secretase inhibitors or expression of a dominant-negative construct led to a significant accumulation of HLA-A2 CTFs. We also identified the PS1/gamma-secretase cleavage product of HLA-A2 CTF, termed HLA-A2 intracellular domain, in cell-free and cell-based experiments. In the absence of proteasome inhibitors, HLA-A2 intracellular domain underwent rapid degrad-ation. These data indicate that MHC I proteins undergo extra-cellular domain cleavage mediated by alpha-secretases and the cleavage product is subsequently cleaved by PS1/gamma-secretase.

Presenilin/γ-secretase and α-secretase-like peptidases cleave human MHC Class I proteins