Elsevier

Biochimie

Volume 107, Part A, December 2014, Pages 66-72
Biochimie

Mini-review
Dealing with damage: Plasma membrane repair mechanisms

https://doi.org/10.1016/j.biochi.2014.08.008Get rights and content

Highlights

  • Mechanical injuries within the plasma membrane are repaired by lysosomal exocytosis.

  • Toxin-induced membrane perforations are shed as microvesicles or endocytosed.

  • Plasmalemmal repair profits from destabilization of the submembranous cytoskeleton.

  • An increase in membrane surface reduces the likelihood of lethal injury.

  • Microvilli and ciliae serve as passive, membrane blebs as active toxin traps.

Abstract

Eukaryotic cells have developed repair mechanisms, which allow them to reseal their membrane in order to prevent the efflux of cytoplasmic constituents and the uncontrolled influx of calcium. After injury, the Ca2+-concentration gradient fulfils a dual function: it provides guidance cues for the repair machinery and directly activates the molecules, which have a repair function. Depending on the nature of injury, the morphology of the cell and the severity of injury, the membrane resealing can be effected by lysosomal exocytosis, microvesicle shedding or a combination of both. Likewise, exocytosis is often followed by the endocytic uptake of lesions. Additionally, since plasmalemmal resealing must be attempted, even after extensive injury in order to prevent cell lysis, the restoration of membrane integrity can be achieved by ceramide-driven invagination of the lipid bilayer, during which the cell is prepared for apoptotic disposal. Plasmalemmal injury can be contained by a surfeit of plasma membrane, which serves as a trap for toxic substances: either passively by an abundance of cellular protrusions, or actively by membrane blebbing.

Introduction

If one contemplates the seemingly effortless performance of an entire organism, one tends to overlook that its smooth operation critically depends on the integrity of its individual components at the cellular level. Damage control mechanisms are a necessity for the survival of eukaryotic cells since breaches in the plasma membrane lead to uncontrolled calcium and potassium influx and to the efflux of cytoplasmic constituents. Hence, either a potent protective shield or the ability to constantly renew the cellular surface are important factors in cellular survival. Fortunately, Nature has developed a number of methods for the prevention of cellular injuries and more than a few strategies for the repair of plasma membrane lesions.

The majority of eukaryotic cells are exposed to biological or chemical damage and/or mechanical injury. Regardless whether the plasma membrane is perforated by bacterial toxins or complement or whether a membrane lesion consists of a ragged hole, the cell needs to initiate repair quickly in order to prevent catastrophic lysis. Plasmalemmal repair either restores the cell to full functionality or at least enables its regulated disposal through apoptotic pathways.

Cultured cells are the logical choice to investigate the individual membrane repair skills and they have faithfully served as model systems for many years [1]. Mechanical lesions elicited by micropipettes, scraping or lasers [2], [3], [4], [5], [6], [7], have been extensively investigated. The cellular reaction to membrane perforation by bacterial toxins or complement has been equally well documented [8], [9], [10], [11], [12], [13].

Section snippets

Mechanisms of plasmalemmal repair (1) or: what happens to the lacerations?

Membrane lesions of irregular shape and size must be patched by reserve membrane fragments which originate from intracellular reservoirs. Initial experiments addressing this mechanism date back almost one century, when the recovery of a mechanically injured marine invertebrate oocyte was brought about “by the formation of a membrane-like film which prevents extension of the injury” [14]. The Ca2+-dependent, homotypic fusion of intracellular vesicles with the plasma membrane was initially

Mechanisms of plasmalemmal repair (2) or: what happens to the pores?

Toxins are essential virulence factors for a large number of pathogens. The largest family (∼30% of all bacterial toxins) are the pore-forming toxins (PFT). Members include the cholesterol-dependent cytolysins as well as numerous toxins, which are secreted by Staphylococcus aureus (α-toxin, leukocidins) [24], [25], [26]. Bacterial pore-forming toxins either generate small (0.5–5 nm) or large (20–100 nm) pores [26], [27]. Cholesterol-dependent cytolysins are characterized not only by the large

Mechanisms of plasmalemmal repair (3) or: what happens to the cytoskeleton?

In contrast to toxin-induced plasmalemmal damage, which remains restricted to the lipid bilayer, mechanical injuries always affect both the plasma membrane and the submembranous cytoskeletal elements, which are tethered to the plasmalemma. The recruitment of GTPases organize the deployment of actin, myosin and microtubules and thereby mediate wound closure in a purse-string like mechanism [58], [59]. Since the upsurge in Ca2+ initiates repair of the lipid bilayer as well as triggering

Mechanisms of avoiding damage or: can injury be anticipated or evaded?

Inside the body, scores of cells are in contact with the hostile and dangerous exterior, yet do not have the privilege of being protected by a keratinized stratified squamous epithelium. In particular the mucosal surfaces of the gastrointestinal and respiratory tract are at risk of being injured. In the airways, the ciliated tracheobronchial epithelium forms the physical basis for local defense [65]. Despite a layer of airway mucus, the inhalation of pathogens exposes the epithelia of the upper

Conclusions

Plasma membrane repair is vital for injured cells: be it to restore functionality or to ensure coordinated apoptosis and well-ordered disposal. Predominantly affected are cells within the organism, which are exposed to mechanical stress or are in contact with bacterial pathogens.

To a certain extent, the cell is capable of making its own repair decisions. These decisions are governed by cellular morphology, the extent of injury, the localisation of membrane damage and the degree of Ca2+-influx.

Acknowledgement

Research in the authors' lab has been supported by the Swiss National Science Foundation.

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