Latent TGFβ complexes are transglutaminase cross-linked to fibrillin to facilitate TGFβ activation

TGF beta superfamily members are potent growth factors in the extracellular matrix with essential roles in all aspects of cellular behaviour. Latent TGF beta binding proteins (LTBPs) are co-expressed with TGF beta, essential for correct folding and secretion of the growth factor, to form large latent complexes. These large latent complexes bind extracellular proteins such as fibrillin for sequestration of TGF beta in the matrix, essential for normal tissue function, and dysregulated TGF beta signalling is a hallmark of many fibrillinopathies. Transglutaminase-2 (TG2) cross-linking of LTBPs is known to play a role in TGF beta activation but the underlying molecular mechanisms are not resolved. Here we show that fibrillin is a matrix substrate for TG2 and that TG2 cross-linked complexes can be formed between fibrillin and LTBP-1 and -3, and their latent TGF beta complexes. The structure of the fibrillin-LTBP1 complex shows that the two elongated proteins interact in a perpendicular arrangement which would allow them to form distal interactions between the matrix and the cell surface. Formation of the cross-link with fibrillin does not change the interaction between latent TGF beta and integrin alpha V beta 6 but does increase TGF beta activation in cell-based assays. The activating effect may be due to direction of the latent complexes to the cell surface by fibrillin, as competition with heparan sulphate can ameliorate the activating effect. Together, these data support that TGF beta activation can be enhanced by covalent tethering of LTBPs to the matrix via fibrillin. (C) 2022 The Author(s). Published by Elsevier B.V.

Automated summary

TGF beta superfamily members play essential roles in cellular behavior, and the cross-linking of latent TGF beta binding proteins (LTBPs) with fibrillin can enhance TGF beta activation, influencing cell and tissue function.