Loss of the Desmosomal Protein Perp Enhances the Phenotypic Effects of Pemphigus Vulgaris Autoantibodies

Abstract

Pemphigus vulgaris (PV) is an autoimmune bullous disease in which autoantibodies against proteins of the desmosomal adhesion complex perturb desmosomal function, leading to intercellular adhesion defects in the oral mucosa and skin. Previous studies have demonstrated a central role for downregulation of the desmosomal cadherin desmoglein 3 (DSG3) in the pathogenesis of PV. However, the effects of non-cadherin desmosomal proteins in modulating the cellular manifestations of PV remain poorly understood. Here, we characterize the expression and functional importance of Perp, a newly discovered tetraspan desmosomal protein, in PV. Our data demonstrate that PV autoantibodies disrupt Perp expression at the membrane and trigger its internalization along with DSG3 into the endosomal pathway, where it is ultimately targeted to the lysosome for degradation. We further show that Perp deficiency exacerbates the pathogenic effects of PV autoantibodies on keratinocytes by enhancing both the depletion of desmosomal DSG3 and intercellular adhesion defects. Together, our findings highlight the importance of non-cadherin desmosomal proteins in modulating PV phenotypes and provide new insight into Perp’s role in the desmosome.

Desmosomes: Regulators of Cellular Signaling and Adhesion in Epidermal Health and Disease

“…The autoimmune skin disorders pemphigus and paraneoplastic pemphigus are associated with the presence of circulating autoantibodies attacking desmosomal components including Dsg1, Dsg3, Dsc3, and possibly Pkp3, bullous pemphigoid antigen 1, envoplakin, periplakin, and Perp (Koulu et al 1984;Amagai et al 1991;Nguyen et al 2009;Mao et al 2010;Yong and Tey 2012;Kalantari-Dehaghi et al 2013) and reviewed recently by several groups (Amagai and Stanley 2012;Grando 2012;Cirillo and Al-Jandan 2013). Although a potential role for antibodies directed against cytoplasmic components in disease pathogenesis has been suggested, the majority of data point to Dsg3 and Dsg1 as the primary targets in pemphigus vulgaris and foliaceus (see Fig.…”

Desmosomal Cadherins and Signaling: Lessons from Autoimmune Disease

“…The involvement of p38MAPK is well established, which may require its downstream kinase MAPKAP kinase 2 (MK2) (Berkowitz et al, 2005(Berkowitz et al, , 2006Mao et al, 2013) and epidermal growth factor receptor (EGF-R) and/or Src signaling (Bektas et al, 2013;Chernyavsky et al, 2007;Frusic-Zlotkin et al, 2006;Tsang et al, 2012b). Other molecules implicated in pemphigus are Akt/mTOR and FAK (Gil et al, 2012;Pretel et al, 2009) as well as JNK (Marchenko et al, 2010), CDK-2 (Lanza et al, 2008), PERP (Nguyen et al, 2009) and factors associated with apoptotic signaling such as caspases 3, 6, 8, and 9 as well as Bcl/Bax and others (Li et al, 2009;Marchenko et al, 2010). However, for most signaling pathways the precise mechanisms by which they reduce Dsg-mediated binding and desmosomal integrity are not well understood.…”

150thAnniversary Series: Desmosomes and Autoimmune Disease, Perspective of Dynamic Desmosome Remodeling and Its Impairments in Pemphigus

“…It should be noted that Dsg3 is phosphorylated transiently before its degradation . PV-IgG-activated signaling molecules found after these fi ndings include EGFR (Bektas et al, 2013;Chernyavsky et al, 2007), Src (Chernyavsky et al, 2007;Cirillo et al, 2014), p38 MAPK (Chernyavsky et al, 2007;Jolly et al, 2010;Spindler et al, 2013), RhoA (Waschke et al, 2006), c-myc (Williamson et al, 2006), PERP (Nguyen et al, 2009), FAK (Gil et al, 2012), Akt/ mTOR (Pretel et al, 2009) and cdk2 (Lanza et al, 2008). Especially, it is worthwhile to note that an anti-Dsg3 antibody, AK23, activates EGFR followed by an increase in Myc levels, events leading keratinocytes to proliferate in association with Dsg3 depletion and acantholysis in AK23-injected mice (Schulze et a., 2012).…”