Targeting Sec61 to Silence Pathogenic Light-Chain Production in AL Amyloidosis
- 1Institut Pasteur, Paris, France
Abstract
Unstable immunoglobulin light chains (LCs) secreted by clonal plasma cells drive organ damage in AL amyloidosis, yet no therapy exist to directly suppress their biosynthesis. Here, we targeted the Sec61 translocon to block LC biogenesis. In patient-derived plasma cells, the Sec61 blocker mycolactone redirected nascent LCs to proteasomal degradation, inducing proteotoxic stress that synergized with bortezomib. In vivo, this combination reduced plasma-cell engraftment and LC secretion but caused toxicity, underscoring the need for Sec61 client selectivity. Proteomic profiling of a model patient-derived plasma cell line treated with the synthetic Sec61 inhibitors A317 and A347 revealed intermediate- and narrow-spectrum client selectivity, respectively, while retaining activity against the LC. However, unlike A317, the more selective A347 failed to inhibit diverse amyloidogenic LCs in a signal-peptide reporter assay. In primary plasma cells from an AL cohort, A317 consistently reduced pathogenic LC production while sparing matched non-malignant bone marrow cells. Together, these findings establish Sec61 as a therapeutic target in AL amyloidosis and identify the need to balance client selectivity with coverage of diverse amyloidogenic LC signal peptides.
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BibTeX
@misc{ricci2026targeting,
title = {{Targeting Sec61 to Silence Pathogenic Light-Chain Production in AL Amyloidosis}},
author = {D. Ricci and C. Veront and I. Valcozzena and M. Despres and A. Nevone and M. Oberkampf and M. Matondo and K. Druart and T. Douche and S. Loulizi and D. Hardy and F. Bugault and M. Capdeville and C. Demangel},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.10.750585},
url = {https://www.biorxiv.org/content/10.64898/2026.09.10.750585v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Targeting Sec61 to Silence Pathogenic Light-Chain Production in AL Amyloidosis
AU - D. Ricci
AU - C. Veront
AU - I. Valcozzena
AU - M. Despres
AU - A. Nevone
AU - M. Oberkampf
AU - M. Matondo
AU - K. Druart
AU - T. Douche
AU - S. Loulizi
AU - D. Hardy
AU - F. Bugault
AU - M. Capdeville
AU - C. Demangel
PY - 2026
DA - 2026/09/10
PB - bioRxiv
DO - 10.64898/2026.09.10.750585
UR - https://www.biorxiv.org/content/10.64898/2026.09.10.750585v1
AB - Unstable immunoglobulin light chains (LCs) secreted by clonal plasma cells drive organ damage in AL amyloidosis, yet no therapy exist to directly suppress their biosynthesis. Here, we targeted the Sec61 translocon to block LC biogenesis. In patient-derived plasma cells, the Sec61 blocker mycolactone redirected nascent LCs to proteasomal degradation, inducing proteotoxic stress that synergized with bortezomib. In vivo, this combination reduced plasma-cell engraftment and LC secretion but caused toxicity, underscoring the need for Sec61 client selectivity. Proteomic profiling of a model patient-derived plasma cell line treated with the synthetic Sec61 inhibitors A317 and A347 revealed intermediate- and narrow-spectrum client selectivity, respectively, while retaining activity against the LC. However, unlike A317, the more selective A347 failed to inhibit diverse amyloidogenic LCs in a signal-peptide reporter assay. In primary plasma cells from an AL cohort, A317 consistently reduced pathogenic LC production while sparing matched non-malignant bone marrow cells. Together, these findings establish Sec61 as a therapeutic target in AL amyloidosis and identify the need to balance client selectivity with coverage of diverse amyloidogenic LC signal peptides.
ER -