Abstract
The annexins, a family of Ca(2+)- and lipid-binding proteins, are involved in a range of intracellular processes. Recent findings have implicated annexin A1 in the resealing of plasmalemmal injuries. Here, we demonstrate that another member of the annexin protein family, annexin A6, is also involved in the repair of plasmalemmal lesions induced by a bacterial pore-forming toxin, streptolysin O. An injury-induced elevation in the intracellular concentration of Ca(2+) ([Ca(2+)](i)) triggers plasmalemmal repair. The highly Ca(2+)-sensitive annexin A6 responds faster than annexin A1 to [Ca(2+)](i) elevation. Correspondingly, a limited plasmalemmal injury can be promptly countered by annexin A6 even without the participation of annexin A1. However, its high Ca(2+) sensitivity makes annexin A6 highly amenable to an unproductive binding to the uninjured plasmalemma; during an extensive injury accompanied by a massive elevation in [Ca(2+)](i), its active pool is severely depleted. In contrast, annexin A1 with a much lower Ca(2+) sensitivity is ineffective at the early stages of injury; however, it remains available for the repair even at high [Ca(2+)](i). Our findings highlight the role of the annexins in the process of plasmalemmal repair; a number of annexins with different Ca(2+)-sensitivities provide a cell with the means to react promptly to a limited injury in its early stages and, at the same time, to withstand a sustained injury accompanied by the continuous formation of plasmalemmal lesions.
Highlights
The annexins are a family of Ca2ϩ-binding proteins expressed in most phyla and species [1,2,3,4]
We show that, similar to annexin A1, annexin A6 is directly involved in the repair of plasmalemmal lesions induced by streptolysin O (SLO)
Annexin A6 Responds Faster to Plasmalemmal Injury Than Annexin A1—An elevation in [Ca2ϩ]i, presumably, the earliest event occurring in the cytoplasm of injured cells [15], leads to the translocation of cytoplasmic annexins to the plasmalemma [16, 19, 23]
Summary
The annexins are a family of Ca2ϩ-binding proteins expressed in most phyla and species [1,2,3,4]. This particular concentration was sufficiently low to allow plasmalemmal resealing in a substantial number of cells (see Fig. 1B) and, at the same time, was high enough to induce [Ca2ϩ]i elevation required for annexin A1 translocation. Careful re-examination of the published images revealed that both annexin A1-containing (YFP, yellow) and annexin A6-containing (CFP, blue) microvesicles were shed from SLO-perforated cells (see supplemental Fig. S2).
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