Why do humans need thrombospondin-1?

Abstract

Matricellular proteins comprise several families of secreted proteins that function in higher animals at the interface between cells and their surrounding extracellular matrix. Targeted gene disruptions that result in loss of viability in mice have revealed critical roles for several matricellular proteins in murine embryonic development, including two members of the cellular communication network (CCN) gene family. In contrast, mice lacking single or multiple members of the thrombospondin (THBS) gene family remain viable and fertile. The frequency of loss of function mutants, identified using human deep exome sequencing data, provided evidence that some of the essential genes in mice, including Ccn1, are also essential genes in humans. However, a deficit in loss of function mutants in humans indicated that THBS1 is also highly loss-intolerant. In addition to roles in embryonic development or adult reproduction, genes may be loss-intolerant in humans because their function is needed to survive environmental stresses that are encountered between birth and reproduction. Laboratory mice live in a protected environment that lacks the exposures to pathogens and injury that humans routinely face. However, subjecting Thbs1^-/- mice to defined stresses has provided valuable insights into functions of thrombospondin-1 that could account for the loss-intolerance of THBS1 in humans. Stress response models using transgenic mice have identified protective functions of thrombospondin-1 in the cardiovascular system (red) and immune defenses (blue) that could account for its intolerance to loss of function mutants in humans.

Keywords: Essential genes; Human genetic variation; Loss of function variants; Matricellular proteins; Thrombospondin-1.

Stress response models using transgenic mice have identified protective functions of thrombospondin-1 in the cardiovascular system (red) and immune defenses (blue) that could account for its intolerance to loss of function mutants in humans

Fig. 1

Thrombospondin-1 functions that may select against LoF mutants in humans. Hemostasis and maintenance of central blood pressure are essential for survival of acute injuries. Both processes are regulated by CD47-dependent thrombospondin-1 signaling, which inhibits the biosynthesis of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS), the activation of soluble guanylate cyclase (sGC) by NO, and the downstream signaling mediated by cGMP-dependent protein kinases in vascular smooth muscle cells and platelets. Thrombospondin-1 also enhances platelet function by preventing the proteolytic inactivation of von Willebrand factor by ADAMTS13. Immune defenses against viral, bacterial, and fungal pathogens are also critical for survival to reproductive age. Thrombospondin-1 regulates innate and adaptive immune responses through CD47, interaction with α6β1 integrin that activates superoxide (O₂⁻) production by NADPH oxidase-2 (Nox2), direct activation of immunosuppressive transforming growth factor-β1 (TGFβ1), and incorporation into supramolecular attack particles that mediate sustained delivery of granzyme B and perforin by NK and CD8 T cells to kill infected cells