Biological role of prolyl 3-hydroxylation in type IV collagen

Elena Pokidysheva, Sergei Boudko, Janice Vranka, Keith Zientek, Kerry Maddox, Markus Moser, Reinhard Fässler, Jerry Ware, Hans Peter Bächinger

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Abstract

Collagens constitute nearly 30% of all proteins in our body. Type IV collagen is a major and crucial component of basement membranes. Collagen chains undergo several posttranslational modifications that are indispensable for proper collagen function. One of these modifications, prolyl 3-hydroxylation, is accomplished by a family of prolyl 3-hydroxylases (P3H1, P3H2, and P3H3). The present study shows that P3H2-null mice are embryonic-lethal by embryonic day 8.5. The mechanism of the unexpectedly early lethality involves the interaction of non-3-hydroxylated embryonic type IV collagen with the maternal platelet-specific glycoprotein VI (GPVI). This interaction results in maternal platelet aggregation, thrombosis of the maternal blood, and death of the embryo. The phenotype is completely rescued by producing double KOs of P3H2 and GPVI. Double nulls are viable and fertile. Under normal conditions, subendothelial collagens bear the GPVI-binding sites that initiate platelet aggregation upon blood exposure during injuries. In type IV collagen, these sites are normally 3-hydroxylated. Thus, prolyl 3-hydroxylation of type IV collagen has an important function preventing maternal platelet aggregation in response to the early developing embryo. A unique link between blood coagulation and the ECM is established. The newly described mechanism may elucidate some unexplained fetal losses in humans, where thrombosis is often observed at the maternal/fetal interface. Moreover, epigenetic silencing of P3H2 in breast cancers implies that the interaction between GPVI and non-3-hydroxylated type IV collagen might also play a role in the progression of malignant tumors and metastasis.

Original languageEnglish (US)
Pages (from-to)161-166
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number1
DOIs
StatePublished - Jan 16 2014

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    Pokidysheva, E., Boudko, S., Vranka, J., Zientek, K., Maddox, K., Moser, M., Fässler, R., Ware, J., & Bächinger, H. P. (2014). Biological role of prolyl 3-hydroxylation in type IV collagen. Proceedings of the National Academy of Sciences of the United States of America, 111(1), 161-166. https://doi.org/10.1073/pnas.1307597111