Actin-cytoskeleton-dependent regulation of desmosomal adhesion in keratinocytes

• Applicants: Professor Dr. Volker Spindler; Professor Dr. Jens Waschke
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology ; Cell Biology
• Term: from 2010 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 170490234

• Final Report Year: 2020

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
  
• (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
  
• (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
  
• (2014) Adducin is required for desmosomal adhesion in keratinocytes, J Biol Chem, 289(21):14925-40
  Rötzer V, Breit A, Waschke J, Spindler V
  
• (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
  
• (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
  
• (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
  
• (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
  
• (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
  
• (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
  
• (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
  
• (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
  
• (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
  
• (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