Serpins flex their muscle: I. Putting the clamps on proteolysis in diverse biological systems

Abstract

Serpins compose the largest superfamily of peptidase inhibitors and are well known as regulators of hemostasis and thrombolysis. Studies using model organisms, from plants to vertebrates, now show that serpins and their unique inhibitory mechanism and conformational flexibility are exploited to control proteolysis in molecular pathways associated with cell survival, development, and host defense. In addition, an increasing number of non-inhibitory serpins are emerging as important elements within a diversity of biological systems by serving as chaperones, hormone transporters, or anti-angiogenic factors.

FIGURE 1.

Intracellular serpins as prosurvival factors. SERPINB6, -B9, and -B13 and C. elegans SRP-6 protect against peptidases released from lysosomes/granules (red) that result in cell death. SRP-6 also inhibits calpains upstream of lysosomal rupture, which are activated by release of calcium (gray) from the endoplasmic reticulum (green) and unidentified stressors.

FIGURE 2.

Serpin regulation of proteolytic cascades involved in Drosophila host defense and development. A, combinations of PRRs for fungi or Gram-positive bacteria activate two different proteolytic cascades leading to the formation of melanin and antimicrobial peptides (AMPs) via the Toll pathway. Microbes activate the Toll pathway independently of PRRs. B, serpin regulation of dorsoventral patterning in the Drosophila embryo (see text). Drosophila serpins and T. molitor serpins (*) are in red; SPs are framed by black boxes. ModSP, modular SP; Psh, Persephone; SAE, Spaetzle-activating enzyme; SPE, Spaetzle-processing enzyme; PPO, pro-PO.