Human macrophage cathepsin β‐mediated C‐terminal cleavage of apolipoprotein α‐I at Ser <sup>228</sup> severely impairs antiatherogenic capacity
Bibliographic record
Abstract
ABSTRACT Apolipoprotein α‐I (apoA‐I) is themajor component of HDLandcentral to the ability of HDLto stimulate ATP‐binding cassette transporter A1 (ABCA1)‐dependent, antiatherogenic export of cholesterol from macrophage foam cells, a key player in the pathology of atherosclerosis. Cell‐mediated modifications of apoA‐I, such as chlorination, nitration, oxidation, and proteolysis, can impair its antiatherogenic function, although it is unknown whether macrophages themselves contribute to such modifications. To investigate this, human monocyte‐derived macrophages (HMDMs) were incubated with human apoA‐I under conditions used to induce cholesterol export. Two‐dimensional gel electrophoresis and Western blot analysis identified that apoA‐I is cleaved (~20–80%) by HMDMs in a time‐dependent manner, generating apoA‐I of lower MW and isoelectric point. Mass spectrometry analysis identified a novel C‐terminal cleavage site of apoA‐I between Ser 228 ‐Phe 229 . Recombinant apoA‐I truncated at Ser 228 demonstrated profound loss of capacity to solubilize lipid and to promoteABCA1‐dependent cholesterol efflux. Protease inhibitors, small interfering RNA knockdown in HMDMs, mass spectrometry analysis, and cathepsin B activity assays identified secreted cathepsin B as responsible for apoA‐I cleavage at Ser 228 . Importantly, C‐terminal cleavage of apoA‐I was also detected in human carotid plaque. Cleavage at Ser 228 is a novel, functionally important post‐translationalmodification of apoA‐Imediated byHMDMsthat limits the antiatherogenic properties of apoA‐I.—Dinnes, D. L.M., White, M. Y., Kockx, M., Traini, M., Hsieh, V., Kim, M.‐J., Hou, L., Jessup, W., Rye, K.‐A., Thaysen‐Andersen, M., Cordwell, S. J., Kritharides, L. Human macrophage cathepsin B‐mediated C‐terminal cleavage of apolipoprotein A‐I at Ser 228 severely impairs antiatherogenic capacity. FASEB J. 30, 4239–4255 (2016). www.fasebj.org
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".