Opposing roles for lipocalins and a CD36 family scavenger receptor in apical extracellular matrix-dependent protection of narrow tube integrity

Belfi, A. C.; Aviles, S. G.; Forman-Rubinsky, R.; Gill, H. K.; Cohen, J. D.; Nawrocka, A.; Bourez, A.; van Antwerpen, P.; Laurent, P.; Sundaram, M. V.

doi:10.1101/2025.07.25.666821

bioRxiv · 10.1101/2025.07.25.666821

Opposing roles for lipocalins and a CD36 family scavenger receptor in apical extracellular matrix-dependent protection of narrow tube integrity

Belfi, A. C.·Aviles, S. G.·Forman-Rubinsky, R.·Gill, H. K.·Cohen, J. D.·Nawrocka, A.·Bourez, A.·van Antwerpen, P.·Laurent, P.·Sundaram, M. V.

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Abstract

All exposed epithelial surfaces, including the walls of internal tubes, are lined by a lipid and glycoprotein-rich apical extracellular matrix (aECM) that helps shape and protect the apical domain. Secreted lipocalins are lipid transporters frequently found within apical compartments. We show that loss of the C. elegans lipocalin LPR-1 disrupts the assembly of another lipocalin, LPR-3, within the pre-cuticle aECM that protects and shapes the narrow excretory duct and pore tubes. LPR-1 is apically secreted and colocalizes with LPR-3 in intracellular vesicles and lysosomes, but unlike LPR-3 it does not detectably incorporate into the aECM. Forward genetic screens for lpr-1 suppressors identified mutations in scav-2, which encodes a transmembrane protein of the CD36 scavenger receptor B family. Loss of scav-2 restored LPR-3 matrix localization and suppressed the lpr-1 tube shaping defect, as well as the tube-shaping defects of a subset of pre-cuticle mutants, but not lpr-3 mutants. A SCAV-2 fusion accumulated at apical surfaces of interfacial epithelial tubes, including the excretory duct and pore, and both tissue-specific suppression of lpr-1 matrix defects and tissue-specific rescue experiments support a local role for SCAV-2 within these tubes. These data demonstrate that LPR-1 and SCAV-2 have opposing effects on narrow tube integrity by altering the content and organization of that tubes luminal aECM, possibly by acting as transporters of an LPR-3 cofactor. These results have broadly relevant implications regarding the importance of lipocalins and scavenger receptors for aECM organization and integrity of the narrowest tubes in the body.

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Belfi, A. C., Aviles, S. G., Forman-Rubinsky, R., Gill, H. K., Cohen, J. D., Nawrocka, A., Bourez, A., van Antwerpen, P., Laurent, P., Sundaram, M. V.. 2025-07-28. Opposing roles for lipocalins and a CD36 family scavenger receptor in apical extracellular matrix-dependent protection of narrow tube integrity. https://doi.org/10.1101/2025.07.25.666821

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