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The complexity and redundancy of epithelial barrier function.

Steinert PM - J. Cell Biol. (2000)

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892-2752, USA. pemast@helix.nih.gov

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How CE assembly proceeds during differentiation in epithelia is still speculative, but extant data have now provided the following working model (Fig. 1)... An early event upon initiation of terminal differentiation is the expression of envoplakin and periplakin (Ruhrberg et al. 1996, Ruhrberg et al. 1997) that become associated together at, and in between, desmosomes... Shortly later, members of the small proline rich (SPR) family of proteins become cross-linked to both envoplakin and involucrin... For example, in the epidermis, the major CE reinforcement proteins are loricrin cross-linked together with lesser amounts of SPRs; in oral epithelia, the CEs are ∼70% SPRs and ∼10% loricrin; and in the hair cuticle, cysteine-rich proteins are used... In addition, in the epidermis, transglutaminase 1 attaches ceramide lipids by ester linkages to involucrin, envoplakin, and periplakin for water barrier function (Marekov and Steinert 1998; Nemes et al. 1999b)... However, it would be of interest to also examine the levels of envoplakin, periplakin, and multiple members of the SPR family, which are typically expressed in stratified squamous epithelia, or repetin or trichohyalin, commonly expressed in the CEs of toughened epithelia, including the epidermis... Whereas the amount of SPRs in CEs varies from <1% in human trunk epidermis, to >10% in palmaplantar and lip epidermis, the sum of loricrin plus SPRs seems to remain constant at ∼85% (Steinert et al. 1998)... How is this incredibly insoluble protein dispatched to the cell periphery for CE assembly? What is the function of the extraordinarily long runs of glycines that are also present on the keratins 1, 2e, and 10, which form the bulk of the mass of the epidermal keratinocyte? Several hundred million years ago, our early vertebrate ancestors crawled out of swamps to begin a new era of life on land... One of their earliest adaptations to this new environment was improved barrier function of their skin... These three new papers, together with a number of other recent studies, suggest that the subsequent evolution of barrier function has not only been bewilderingly complex, but compensatory backup systems have been built in to substitute in the absence of one or other of the major players.

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A model of the epidermal CE. Loricrin (white circles) is the major CE protein, admixed with small amounts of SPRs 1 and 2 (pink ellipsoids). Together, these constitute ∼85% of the CE and represent the final reinforcement stage of CE assembly. However, the number of layers of loricrin remains unresolved. It may be one (Jarnik et al. 1998), in which case the axial ratio of each loricrin molecule should be ∼1:4, or at least two and up to four, if the loricrin molecules are spherical. In the case of the loricrin−/− mice (Koch et al. 2000), it is anticipated that SPRs and some other proteins (blue circles), such as repetin and trichohyalin, compensate for absent loricrin. It is speculated that the loricrin–SPR complex is cross-linked onto a scaffold composed of several proteins cross-linked together at or near the plasma membrane, including keratin filaments (long red rod), envoplakin (red box), periplakin (blue box), and involucrin (green box), perhaps by transglutaminase 1 (green circles). If these do form a redundant scaffold, this could explain the individual phenotypes of the involucrin−/− (Djian et al. 2000) and envoplakin−/− (Määttä, A., and F. Watt, personal communication) mice, as one may compensate for the absence of the other. The yellow rods denote ceramide lipids that become ester-linked by transglutaminase 1 onto involucrin, envoplakin, and periplakin. These replace the plasma membrane of the cornified cell and are important for interdigitation with extracellular lipids that together confer water barrier function. Modified from Nemes and Steinert 1999.
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Figure 1: A model of the epidermal CE. Loricrin (white circles) is the major CE protein, admixed with small amounts of SPRs 1 and 2 (pink ellipsoids). Together, these constitute ∼85% of the CE and represent the final reinforcement stage of CE assembly. However, the number of layers of loricrin remains unresolved. It may be one (Jarnik et al. 1998), in which case the axial ratio of each loricrin molecule should be ∼1:4, or at least two and up to four, if the loricrin molecules are spherical. In the case of the loricrin−/− mice (Koch et al. 2000), it is anticipated that SPRs and some other proteins (blue circles), such as repetin and trichohyalin, compensate for absent loricrin. It is speculated that the loricrin–SPR complex is cross-linked onto a scaffold composed of several proteins cross-linked together at or near the plasma membrane, including keratin filaments (long red rod), envoplakin (red box), periplakin (blue box), and involucrin (green box), perhaps by transglutaminase 1 (green circles). If these do form a redundant scaffold, this could explain the individual phenotypes of the involucrin−/− (Djian et al. 2000) and envoplakin−/− (Määttä, A., and F. Watt, personal communication) mice, as one may compensate for the absence of the other. The yellow rods denote ceramide lipids that become ester-linked by transglutaminase 1 onto involucrin, envoplakin, and periplakin. These replace the plasma membrane of the cornified cell and are important for interdigitation with extracellular lipids that together confer water barrier function. Modified from Nemes and Steinert 1999.

Mentions: To date, cell biological, biochemical, and protein sequencing studies have shown that at least 20 proteins are used to assemble CEs. How CE assembly proceeds during differentiation in epithelia is still speculative, but extant data have now provided the following working model (Fig. 1). An early event upon initiation of terminal differentiation is the expression of envoplakin and periplakin (Ruhrberg et al. 1996, Ruhrberg et al. 1997) that become associated together at, and in between, desmosomes. A short time later, involucrin is expressed, which was the first described CE precursor (Rice and Green 1979). Data from this laboratory have suggested that it binds spontaneously to membranes in a Ca2+ dependent manner (Nemes et al. 1999a). Another early expression product is the transglutaminase 1 enzyme (Kim et al. 1995), which self-assembles onto membranes by way of its acyl lipid adducts. As localized Ca2+ concentrations rise, the enzyme cross-links involucrin to form a two-dimensional head-to-head and head-to-tail oligomeric mesh, and involucrin to envoplakin (and perhaps periplakin; LaCelle et al. 1998; Steinert and Marekov 1999). Shortly later, members of the small proline rich (SPR) family of proteins become cross-linked to both envoplakin and involucrin. Eventually, this amalgam spreads across the inner surface of the plasma membrane, including the desmosomes, so that many cell junctional proteins, including desmoplakin, annexin I, and keratin intermediate filaments become cross-linked too. Together, these form a uniform layer that serves as a template or scaffold for subsequent maturation or reinforcement stages of CE assembly (Yaffe et al. 1992; Ruhrberg et al. 1997; Steinert and Marekov 1999). This process varies between epithelia, presumably in concert with tissue-specific requirements. For example, in the epidermis, the major CE reinforcement proteins are loricrin cross-linked together with lesser amounts of SPRs; in oral epithelia, the CEs are ∼70% SPRs and ∼10% loricrin; and in the hair cuticle, cysteine-rich proteins are used. In addition, in the epidermis, transglutaminase 1 attaches ceramide lipids by ester linkages to involucrin, envoplakin, and periplakin for water barrier function (Marekov and Steinert 1998; Nemes et al. 1999b).


The complexity and redundancy of epithelial barrier function.

Steinert PM - J. Cell Biol. (2000)

A model of the epidermal CE. Loricrin (white circles) is the major CE protein, admixed with small amounts of SPRs 1 and 2 (pink ellipsoids). Together, these constitute ∼85% of the CE and represent the final reinforcement stage of CE assembly. However, the number of layers of loricrin remains unresolved. It may be one (Jarnik et al. 1998), in which case the axial ratio of each loricrin molecule should be ∼1:4, or at least two and up to four, if the loricrin molecules are spherical. In the case of the loricrin−/− mice (Koch et al. 2000), it is anticipated that SPRs and some other proteins (blue circles), such as repetin and trichohyalin, compensate for absent loricrin. It is speculated that the loricrin–SPR complex is cross-linked onto a scaffold composed of several proteins cross-linked together at or near the plasma membrane, including keratin filaments (long red rod), envoplakin (red box), periplakin (blue box), and involucrin (green box), perhaps by transglutaminase 1 (green circles). If these do form a redundant scaffold, this could explain the individual phenotypes of the involucrin−/− (Djian et al. 2000) and envoplakin−/− (Määttä, A., and F. Watt, personal communication) mice, as one may compensate for the absence of the other. The yellow rods denote ceramide lipids that become ester-linked by transglutaminase 1 onto involucrin, envoplakin, and periplakin. These replace the plasma membrane of the cornified cell and are important for interdigitation with extracellular lipids that together confer water barrier function. Modified from Nemes and Steinert 1999.
© Copyright Policy
Related In: Results  -  Collection

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Figure 1: A model of the epidermal CE. Loricrin (white circles) is the major CE protein, admixed with small amounts of SPRs 1 and 2 (pink ellipsoids). Together, these constitute ∼85% of the CE and represent the final reinforcement stage of CE assembly. However, the number of layers of loricrin remains unresolved. It may be one (Jarnik et al. 1998), in which case the axial ratio of each loricrin molecule should be ∼1:4, or at least two and up to four, if the loricrin molecules are spherical. In the case of the loricrin−/− mice (Koch et al. 2000), it is anticipated that SPRs and some other proteins (blue circles), such as repetin and trichohyalin, compensate for absent loricrin. It is speculated that the loricrin–SPR complex is cross-linked onto a scaffold composed of several proteins cross-linked together at or near the plasma membrane, including keratin filaments (long red rod), envoplakin (red box), periplakin (blue box), and involucrin (green box), perhaps by transglutaminase 1 (green circles). If these do form a redundant scaffold, this could explain the individual phenotypes of the involucrin−/− (Djian et al. 2000) and envoplakin−/− (Määttä, A., and F. Watt, personal communication) mice, as one may compensate for the absence of the other. The yellow rods denote ceramide lipids that become ester-linked by transglutaminase 1 onto involucrin, envoplakin, and periplakin. These replace the plasma membrane of the cornified cell and are important for interdigitation with extracellular lipids that together confer water barrier function. Modified from Nemes and Steinert 1999.
Mentions: To date, cell biological, biochemical, and protein sequencing studies have shown that at least 20 proteins are used to assemble CEs. How CE assembly proceeds during differentiation in epithelia is still speculative, but extant data have now provided the following working model (Fig. 1). An early event upon initiation of terminal differentiation is the expression of envoplakin and periplakin (Ruhrberg et al. 1996, Ruhrberg et al. 1997) that become associated together at, and in between, desmosomes. A short time later, involucrin is expressed, which was the first described CE precursor (Rice and Green 1979). Data from this laboratory have suggested that it binds spontaneously to membranes in a Ca2+ dependent manner (Nemes et al. 1999a). Another early expression product is the transglutaminase 1 enzyme (Kim et al. 1995), which self-assembles onto membranes by way of its acyl lipid adducts. As localized Ca2+ concentrations rise, the enzyme cross-links involucrin to form a two-dimensional head-to-head and head-to-tail oligomeric mesh, and involucrin to envoplakin (and perhaps periplakin; LaCelle et al. 1998; Steinert and Marekov 1999). Shortly later, members of the small proline rich (SPR) family of proteins become cross-linked to both envoplakin and involucrin. Eventually, this amalgam spreads across the inner surface of the plasma membrane, including the desmosomes, so that many cell junctional proteins, including desmoplakin, annexin I, and keratin intermediate filaments become cross-linked too. Together, these form a uniform layer that serves as a template or scaffold for subsequent maturation or reinforcement stages of CE assembly (Yaffe et al. 1992; Ruhrberg et al. 1997; Steinert and Marekov 1999). This process varies between epithelia, presumably in concert with tissue-specific requirements. For example, in the epidermis, the major CE reinforcement proteins are loricrin cross-linked together with lesser amounts of SPRs; in oral epithelia, the CEs are ∼70% SPRs and ∼10% loricrin; and in the hair cuticle, cysteine-rich proteins are used. In addition, in the epidermis, transglutaminase 1 attaches ceramide lipids by ester linkages to involucrin, envoplakin, and periplakin for water barrier function (Marekov and Steinert 1998; Nemes et al. 1999b).

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892-2752, USA. pemast@helix.nih.gov

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

How CE assembly proceeds during differentiation in epithelia is still speculative, but extant data have now provided the following working model (Fig. 1)... An early event upon initiation of terminal differentiation is the expression of envoplakin and periplakin (Ruhrberg et al. 1996, Ruhrberg et al. 1997) that become associated together at, and in between, desmosomes... Shortly later, members of the small proline rich (SPR) family of proteins become cross-linked to both envoplakin and involucrin... For example, in the epidermis, the major CE reinforcement proteins are loricrin cross-linked together with lesser amounts of SPRs; in oral epithelia, the CEs are ∼70% SPRs and ∼10% loricrin; and in the hair cuticle, cysteine-rich proteins are used... In addition, in the epidermis, transglutaminase 1 attaches ceramide lipids by ester linkages to involucrin, envoplakin, and periplakin for water barrier function (Marekov and Steinert 1998; Nemes et al. 1999b)... However, it would be of interest to also examine the levels of envoplakin, periplakin, and multiple members of the SPR family, which are typically expressed in stratified squamous epithelia, or repetin or trichohyalin, commonly expressed in the CEs of toughened epithelia, including the epidermis... Whereas the amount of SPRs in CEs varies from <1% in human trunk epidermis, to >10% in palmaplantar and lip epidermis, the sum of loricrin plus SPRs seems to remain constant at ∼85% (Steinert et al. 1998)... How is this incredibly insoluble protein dispatched to the cell periphery for CE assembly? What is the function of the extraordinarily long runs of glycines that are also present on the keratins 1, 2e, and 10, which form the bulk of the mass of the epidermal keratinocyte? Several hundred million years ago, our early vertebrate ancestors crawled out of swamps to begin a new era of life on land... One of their earliest adaptations to this new environment was improved barrier function of their skin... These three new papers, together with a number of other recent studies, suggest that the subsequent evolution of barrier function has not only been bewilderingly complex, but compensatory backup systems have been built in to substitute in the absence of one or other of the major players.

Show MeSH
Related in: MedlinePlus