Actin-cytoskeleton-dependent regulation of desmosomal adhesion in keratinocytes
Cell Biology
Final Report Abstract
We addressed the main points of our grant proposal and gathered further insights into two overlapping sets of mechanisms regulating desmosomal adhesion. Using different deficiency models, we established a crucial role of the actin cytoskeleton for desmosomal function. We demonstrated novel concepts how the actin-binding proteins adducin and cortactin modulate keratinocyte adhesion, resistance against mechanical load on cellular and tissue level, and desmosome plasticity. These mechanisms at least in part take place on the level of desmosomal contact formation and require shaping of the mobility of free desmosomal molecules in the membrane. Moreover, linked to these processes, we described two different signaling complexes regulating desmosomal adhesion under conditions of wound healing and in pemphigus pathogenesis. The Dsg3/p38MAPK complex is activated by pemphigus autoantibodies and contributes to loss of cell adhesion. Besides, upon loss of Dsg3 binding, the complex contributes to keratinocyte migration and wound healing. This function is different to the Dsg3/E-cadherin/Src complex, which is located outside of desmosomes and appears to be important for desmosome formation in a process which also involves cortactin. The data show that signaling, cytoskeletal function and cell adhesion are tightly linked both in physiological and diseased states. Taken together, a complex picture can be envisaged in which pemphigus autoantibodies modulate signaling pathways via Dsg3-based signaling complexes such as p38MAPK, which inhibits RhoA/Rho kinase signaling and converges on adducin similar to PKC activation. Other signaling pathways such as Src interfere with cortactin function, which similar to adducin is important for new desmosomal contacts. Collectively, our results give novel insights into the regulation of desmosome function in healthy tissue. On disease level, they contribute to the current understanding that diseases such as pemphigus compromise desmosome function by profoundly altering the turn-over of desmosomes.
Publications
- (2013) Desmoglein 2 is less important than Dsg3 for keratinocyte cohesion, PLOS One, 8(1): e53739
Hartlieb E, Partilla M, Vigh B, Spindler V, Waschke J
(See online at https://doi.org/10.1371/journal.pone.0053739) - (2013) Peptide-mediated desmoglein 3 crosslinking prevents pemphigus vulgaris autoantibody-induced skin blistering, J Clin Invest, 123(2):800–811
Spindler V, Rötzer V, Dehner C, Kempf B, Gliem M, Radeva M, Hartlieb E, Harms GS, Schmidt E, Waschke J
(See online at https://doi.org/10.1172/JCI60139) - (2014) A desmoplakin point mutation with enhanced keratin association ameliorates pemphigus vulgaris autoantibody-mediated loss of cell cohesion, Am J Pathol, 184(9):2528-36
Dehner C, Rötzer V, Waschke J, Spindler V
(See online at https://doi.org/10.1016/j.ajpath.2014.05.016) - (2014) Adducin is required for desmosomal adhesion in keratinocytes, J Biol Chem, 289(21):14925-40
Rötzer V, Breit A, Waschke J, Spindler V
(See online at https://doi.org/10.1074/jbc.M113.527127) - (2014) Desmoglein 2 compensates for desmoglein 3 but does not control cell adhesion via regulation of p38-mitogen-activated protein-kinase in keratinocytes, J Biol Chem, 289(24):17043-17053
Hartlieb E, Rötzer V, Radeva M, Spindler V, Waschke J
(See online at https://doi.org/10.1074/jbc.m113.489336) - (2014) Plakoglobin but not desmoplakin regulates keratinoycte cohesion via p38MAPK signaling, J Invest Dermatol, 134(6):1655-64
Spindler V, Dehner C, Hübner S, Waschke J
(See online at https://doi.org/10.1038/jid.2014.21) - (2015) Atomic force microscopy identifies regions of distinct desmoglein 3 adhesive properties on living keratinocytes. Nanomedicine, 11, 511-520
Vielmuth F, Hartlieb E, Kugelmann D, Waschke J, Spindler V
(See online at https://doi.org/10.1016/j.nano.2014.10.006) - (2015) E-cadherin and Src associate with extradesmosomal Dsg3 and modulate desmosome assembly and adhesion, Cell Mol Life Sci;72(24):4885-97
Rötzer, V., Hartlieb E, Vielmuth F, Gliem M., Spindler V, Waschke J
(See online at https://doi.org/10.1007/s00018-015-1977-0) - (2015) Loss of desmoglein binding is not sufficient for keratinocyte dissociation in pemphigus, J Invest Dermatol, 135(12):3068-77
Vielmuth F, Waschke J, Spindler V
(See online at https://doi.org/10.1038/jid.2015.324) - (2016) Desmoglein 3-dependent signaling regulates keratinocyte migration and wound healing. J. Invest. Dermatol.; 2016; J Invest Dermatol.; 136(1):301-10
Rötzer V, Hartlieb E, Winkler J, Walter E, Schlipp A, Sardy M, Spindler V, Waschke J
(See online at https://doi.org/10.1038/JID.2015.380) - (2018) Keratin Retraction and Desmoglein3 Internalization Independently Contribute to Autoantibody- Induced Cell Dissociation in Pemphigus Vulgaris. Front Immunol. 9:858
Schlögl E, Radeva MY, Vielmuth F, Schinner C, Waschke J, Spindler V
(See online at https://doi.org/10.3389/fimmu.2018.00858) - (2018). Keratins regulate the adhesive properties of desmosomal cadherins through signaling. J Invest Dermatol 138(1):121-131
Vielmuth F, Wanuske MT, Radeva MY, Hiermaier M, Kugelmann D, Walter E, Buechau F, Magin TM, Waschke J, Spindler V
(See online at https://doi.org/10.1016/j.jid.2017.08.033) - (2019) Role of Src and cortactin in pemphigus skin blistering. Front Immunol.10:626
Kugelmann D, Rötzer V, Walter E, Egu DT, Fuchs M, Vielmuth F, Vargas-Robles H, Schnoor M, Hertl M, Eming R, Rottner K, Schmidt A, Spindler V, Waschke J
(See online at https://doi.org/10.3389/fimmu.2019.00626) - (2020). The actin-binding protein alpha-aducin modulates desmosomal turnover and function. J Invest Dermatol.
Hiermaier M, Kliewe F, Schinner C, Stüdle C, Maly IP, Wanuske MT, Rötzer V, Endlich N, Vielmuth F, Waschke J, Spindler V
(See online at https://doi.org/10.1016/j.jid.2020.09.022)
