Transglutaminase mediated asprosin oligomerization allows its tissue storage as fibers

Morcos, Y. A.; Pryymachuk, G.; Hoffmann, T.; Luetke, S.; Gerken, A.; Piekarek, N.; Odenthal, M.; Drebber, U.; Bloch, W.; Callewaert, B.; Paulsson, M.; Hucklenbruch-Rother, E.; Sengle, G.

doi:10.1101/2022.01.04.474899

bioRxiv · 10.1101/2022.01.04.474899

Transglutaminase mediated asprosin oligomerization allows its tissue storage as fibers

Morcos, Y. A.·Pryymachuk, G.·Hoffmann, T.·Luetke, S.·Gerken, A.·Piekarek, N.·Odenthal, M.·Drebber, U.·Bloch, W.·Callewaert, B.·Paulsson, M.·Hucklenbruch-Rother, E.·Sengle, G.

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Abstract

Asprosin, the C-terminal furin cleavage product of profibrillin-1, was reported to act as a hormone that circulates at nanomolar levels and is recruited to the liver where it induces G protein-coupled activation of the cAMP-PKA pathway and stimulates rapid glucose release into the circulation. Although derived upon C-terminal cleavage of fibrillin-1, a multidomain extracellular matrix glycoprotein with a ubiquitous distribution in connective tissues, little is known about the mechanisms controlling the bioavailability of asprosin in tissues. In the current view, asprosin is mainly produced by white adipose tissue from where it is released into the blood in monomeric form. Here, by employing newly generated specific asprosin antibodies we monitored the distribution pattern of asprosin in human and murine connective tissues such as placenta, and muscle. Thereby we detected the presence of asprosin positive extracellular fibers. Further, by screening established cell lines for asprosin synthesis we found that most cells derived from musculoskeletal tissues render asprosin into an oligomerized form. Our analyses show that asprosin already multimerizes intracellularly, but that stable multimerization via covalent bonds is facilitated by transglutaminase activity. Further, asprosin fiber formation requires an intact fibrillin-1 fiber network for proper linear deposition. Our data suggest a new extracellular storage mechanism of asprosin in an oligomerized form which may regulate its cellular bioavailability in tissues.

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Morcos, Y. A., Pryymachuk, G., Hoffmann, T., Luetke, S., Gerken, A., Piekarek, N., Odenthal, M., Drebber, U., Bloch, W., Callewaert, B., Paulsson, M., Hucklenbruch-Rother, E., Sengle, G.. 2022-01-04. Transglutaminase mediated asprosin oligomerization allows its tissue storage as fibers. https://doi.org/10.1101/2022.01.04.474899

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