Hemidesmosomes are multiprotein complexes that facilitate the stable adhesion of basal epithelial cells to the underlying basement membrane. The mechanical stability of hemidesmosomes relies on multiple interactions of a few protein components that form a membrane-embedded tightly-ordered complex. The core of this complex is provided by integrin α6β4 and P1a, an isoform of the cytoskeletal linker protein plectin that is specifically associated with hemidesmosomes. Integrin α6β4 binds to the extracellular matrix protein laminin-332, whereas P1a forms a bridge to the cytoplasmic keratin intermediate filament network. Other important components are BPAG1e, the epithelial isoform of bullous pemphigoid antigen 1, BPAG2, a collagen-type transmembrane protein and CD151. Inherited or acquired diseases in which essential components of the hemidesmosome are missing or structurally altered result in tissue fragility and blistering. Modulation of hemidesmosome function is of crucial importance for a variety of biological processes, such as terminal differentiation of basal keratinocytes and keratinocyte migration during wound healing and carcinoma invasion. Here, we review the molecular characteristics of the proteins that make up the hemidesmosome core structure and summarize the current knowledge about how their assembly and turnover are regulated by transcriptional and post-translational mechanisms.

Integrin‐based mechanotransduction involves a complex focal adhesion (FA)‐associated machinery that is able to detect and respond to forces exerted either through components of the extracellular matrix or the intracellular contractile actomyosin network. Here, we show a hitherto unrecognized regulatory role of vimentin intermediate filaments (IFs) in this process. By studying fibroblasts in which vimentin IFs were decoupled from FAs, either because of vimentin deficiency (V0) or loss of vimentin network anchorage due to deficiency in the cytolinker protein plectin (P0), we demonstrate attenuated activation of the major mechanosensor molecule FAK and its downstream targets Src, ERK1/2, and p38, as well as an up‐regulation of the compensatory feedback loop acting on RhoA and myosin light chain. In line with these findings, we show strongly reduced FA turnover rates in P0 fibroblasts combined with impaired directional migration, formation of protrusions, and up‐regulation of “stretched” high‐affinity integrin complexes. By exploiting tension‐independent conditions, we were able to mechanistically link these defects to diminished cytoskeletal tension in both P0 and V0 cells. Our data provide important new insights into molecular mechanisms underlying cytoskeleton‐regulated mechanosensing, a feature that is fundamental for controlled cell movement and tumor progression.—Gregor, M., Osmanagic‐Myers, S., Burgstaller, G., Wolfram, M., Fischer, I., Walko, G., Resch, G. P., Jörgl, A., Herrmann, H., Wiche, G. Mechanosensing through focal adhesion‐anchored intermediate filaments. FASEB J. 28, 715–729 (2014). www.fasebj.org

Hemidesmosomes are multiprotein complexes that facilitate the stable adhesion of basal epithelial cells to the underlying basement membrane. The mechanical stability of hemidesmosomes relies on multiple interactions of a few protein components that form a membrane-embedded tightly-ordered complex. The core of this complex is provided by integrin α6β4 and P1a, an isoform of the cytoskeletal linker protein plectin that is specifically associated with hemidesmosomes. Integrin α6β4 binds to the extracellular matrix protein laminin-332, whereas P1a forms a bridge to the cytoplasmic keratin intermediate filament network. Other important components are BPAG1e, the epithelial isoform of bullous pemphigoid antigen 1, BPAG2, a collagen-type transmembrane protein and CD151. Inherited or acquired diseases in which essential components of the hemidesmosome are missing or structurally altered result in tissue fragility and blistering. Modulation of hemidesmosome function is of crucial importance for a variety of biological processes, such as terminal differentiation of basal keratinocytes and keratinocyte migration during wound healing and carcinoma invasion. Here, we review the molecular characteristics of the proteins that make up the hemidesmosome core structure and summarize the current knowledge about how their assembly and turnover are regulated by transcriptional and post-translational mechanisms.

Dysfunction of plectin, a 500-kD cytolinker protein, leads to skin blistering and muscular dystrophy. Using conditional gene targeting in mice, we show that plectin deficiency results in progressive degenerative alterations in striated muscle, including aggregation and partial loss of intermediate filament (IF) networks, detachment of the contractile apparatus from the sarcolemma, profound changes in myofiber costameric cytoarchitecture, and decreased mitochondrial number and function. Analysis of newly generated plectin isoform–specific knockout mouse models revealed that IF aggregates accumulate in distinct cytoplasmic compartments, depending on which isoform is missing. Our data show that two major plectin isoforms expressed in muscle, plectin 1d and 1f, integrate fibers by specifically targeting and linking desmin IFs to Z-disks and costameres, whereas plectin 1b establishes a linkage to mitochondria. Furthermore, disruption of Z-disk and costamere linkages leads to the pathological condition of epidermolysis bullosa with muscular dystrophy. Our findings establish plectin as the major organizer of desmin IFs in myofibers and provide new insights into plectin- and desmin-related muscular dystrophies.

Plectin is a major intermediate filament (IF)–based cytolinker protein that stabilizes cells and tissues mechanically, regulates actin filament dynamics, and serves as a scaffolding platform for signaling molecules. In this study, we show that plectin deficiency is a cause of aberrant keratin cytoskeleton organization caused by a lack of orthogonal IF cross-linking. Keratin networks in plectin-deficient cells were more susceptible to osmotic shock–induced retraction from peripheral areas, and their okadaic acid–induced disruption (paralleled by stress-activated MAP kinase p38 activation) proceeded faster. Basal activities of the MAP kinase Erk1/2 and of the membrane-associated upstream protein kinases c-Src and PKCδ were significantly elevated, and increased migration rates, as assessed by in vitro wound-closure assays and time-lapse microscopy, were observed. Forced expression of RACK1, which is the plectin-binding receptor protein for activated PKCδ, in wild-type keratinocytes elevated their migration potential close to that of plectin-null cells. These data establish a link between cytolinker-controlled cytoarchitecture/scaffolding functions of keratin IFs and specific MAP kinase cascades mediating distinct cellular responses.