Clinical Implications•Desmoglein 1 (DSG1)−mediated epidermal stratification requires retromer-mediated endosomal recycling.•Retromer chaperone rescues severe dermatitis, multiple allergies, and metabolic wasting (SAM)−associated desmoglein 1 defects in vitro.•Retromer cargo GLUT1 is altered in Dsg1−/− mice and the skin of patients with SAM.View Large Image Figure ViewerDownload Hi-res image Download (PPT) •Desmoglein 1 (DSG1)−mediated epidermal stratification requires retromer-mediated endosomal recycling.•Retromer chaperone rescues severe dermatitis, multiple allergies, and metabolic wasting (SAM)−associated desmoglein 1 defects in vitro.•Retromer cargo GLUT1 is altered in Dsg1−/− mice and the skin of patients with SAM. As the outermost layer of the skin, the epidermis is an essential barrier against mechanical insult, water loss, infection from microbial pathogens, exposure to toxins, and UVR from sunlight. Because the epidermal barrier requires functional integration of mechanical and immune signaling, interference with keratinocyte (KC) cytoarchitecture can impair both tissue integrity and immune function, resulting in inflammation and associated pain and itch. Thus, it is not surprising that many of the therapeutics developed to treat skin disorders target the inflammatory response. Less attention has been paid to the therapeutic targeting of aberrant structural components associated with disease causation. A major target for skin disease is the desmosome, an intercellular adhesive complex that reinforces skin integrity and is essential for the maintenance of the skin barrier. Desmosomes comprise transmembrane adhesive proteins called desmosomal cadherins that bind to armadillo and plaque proteins to anchor intermediate filaments to the plasma membrane, thus creating a supracellular desmosome−keratin intermediate filaments scaffolding essential for conferring mechanical integrity to the epidermis. In addition to its structural importance, this extensive network impinges on multiple intracellular signaling pathways that guide skin development and homeostasis and can serve as a sentinel of the immune system. Thus, interfering with this network and its individual components through hereditary, autoimmune, and toxin-mediated mechanisms leads to a variety of bullous, acantholytic, hyperkeratotic, and inflammatory disorders. The most common treatment for desmosome-related diseases includes monotherapy or dual therapy with systemic glucocorticoids and immunosuppressants. In addition, preclinical studies in mouse models have shown that pharmacological inhibition of a number of downstream signaling effectors prevents pemphigus-induced blistering (Hegazy et al., 2022bHegazy M. Perl A.L. Svoboda S.A. Green K.J. Desmosomal cadherins in health and disease.Annu Rev Pathol. 2022; 17: 47-72Google Scholar). However, clinical trials have largely failed owing to the side effects of the treatments or insufficient sample size. Thus, there is a great need to explore new ways to target desmosome dysfunction and related skin disorders. One potential therapeutic target that is less well-studied in skin biology is the endosomal trafficking system. The endosomal trafficking machinery ensures that transmembrane proteins are properly processed and translocated/recycled to the plasma membrane, where they can function to recruit other binding partners and signaling effectors. Although the importance of specific intracellular trafficking pathways in the epidermis is poorly understood, there have been reports that disruption of the endolysosomal machinery results in epidermal differentiation defects associated with neurocutaneous disorders such as CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome) and MEDNIK (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratodermia) syndrome (Mahanty and Setty, 2021Mahanty S. Setty S.R.G. Epidermal lamellar body biogenesis: insight into the roles of Golgi and lysosomes.Front Cell Dev Biol. 2021; 9701950Google Scholar). Indeed, desmosomes are not static while providing mechanical strength for the epidermis. Junctional remodeling allows the epidermis to adapt to developmental and external signals. Therefore, understanding how alterations in desmosome dynamics contribute to disease pathogenesis may guide the development of new strategies to ameliorate the effects resulting from desmosome dysfunction. In the study by Hegazy et al., 2022aHegazy M. Koetsier J.L. Huffine A.L. Broussard J.A. Godsel B.M. Cohen-Barak E. et al.Epidermal stratification requires retromer-mediated desmoglein-1 recycling.Dev Cell. 2022; 57: 2683-2698.e8Google Scholar titled “Epidermal stratification requires retromer-mediated Desmoglein-1 recycling,” we identified an endosomal trafficking complex called the retromer as having a role in epidermal development and maintenance by promoting recycling of the desmosomal cadherin, desmoglein 1 (DSG1) (Figure 1a). The retromer has ancient roots, having first been identified in yeast. The mammalian retromer is highly conserved, with the core retromer component being the VPS35−VPS29−VPS26 trimer, also known as the cargo-selective complex (CSC). The retromer CSC associates with higher eukaryotic-specific accessory proteins, which can modulate the retromer CSC’s endosomal membrane recruitment, cargo recognition, and cytoskeleton attachment (Small and Petsko, 2015Small S.A. Petsko G.A. Retromer in Alzheimer disease, Parkinson disease and other neurological disorders.Nat Rev Neurosci. 2015; 16: 126-132Google Scholar). In a protein interaction screen for the desmosomal cadherin, DSG1, we found the retromer component VPS35. Using loss-of-function approaches targeting this and another core retromer component VPS29, we showed that association with the retromer was required for DSG1’s intracellular membrane dynamics and recycling to the plasma membrane, revealing DSG1 as a newly identified cargo for the retromer machinery. Furthermore, interference with retromer function impaired DSG1’s known function in promoting KC differentiation and the transit of basal KCs to the next superficial layer in a process called delamination, underscoring the importance of the retromer in supporting DSG1 functions in the epidermis. We concluded that the retromer plays a vital role in the regeneration of the multilayered epidermis in part by associating with and recycling DSG1 to drive epidermal stratification and differentiation. Retromer dysfunction is most commonly understood to be associated with a growing number of neurological and neurodegenerative disorders, including Parkinson’s disease and Alzheimer’s disease. Thus, there has been great interest and progress in the development of small-molecule pharmacological chaperones that stabilize the retromer complex to increase retromer function. The initial drugs developed by Gregory Petsko and Scott Small showed much promise in this regard, and newer compounds with increased efficacy and reduced toxicity are being developed. In vitro and in vivo delivery of small-molecule retromer chaperones ameliorated common pathological features in Alzheimer’s disease and amyotrophic lateral sclerosis models (Carosi et al., 2021Carosi J.M. Denton D. Kumar S. Sargeant T.J. Retromer dysfunction at the nexus of tauopathies.Cell Death Differ. 2021; 28: 884-899Google Scholar; Small and Petsko, 2015Small S.A. Petsko G.A. Retromer in Alzheimer disease, Parkinson disease and other neurological disorders.Nat Rev Neurosci. 2015; 16: 126-132Google Scholar). These preclinical studies illustrate the feasibility of targeting the retromer and ameliorating the features of neurodegenerative disorders. Until recently, little was known about the retromer’s importance in the epidermis other than in the context of human papillomavirus infection. However, we hypothesized that the retromer chaperones developed to treat neurological disorders may be useful for certain skin diseases. As a test case, we were particularly interested in their potential use for improving DSG1 function in a systemic inflammatory skin disease called severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, caused by mutations in the DSG1 gene. Disease-causing mutations give rise to less stable truncated forms of DSG1 or DSG1 that accumulate in intracellular membrane compartments because of a mutation in the N-terminal signal sequence, resulting in perturbed trafficking. In addition to interfering with desmosomal adhesion, loss of DSG1 function was associated with an inflammatory signature resembling that of patients with psoriasis (Godsel et al., 2022Godsel L.M. Roth-Carter Q.R. Koetsier J.L. Tsoi L.C. Huffine A.L. Broussard J.A. et al.Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor.J Clin Invest. 2022; 132e144363Google Scholar). Indeed, treatment of these patients with suppressors of the psoriasis-associated cytokines IL-12/23 or IL-17A resulted in a dramatic improvement in patient skin inflammation. Targeting these inflammatory pathways is also beneficial in certain other ichthyoses, although treatments can fail even in the presence of a T helper 17 (Th17) inflammatory profile (Horikawa and Amagai, 2022Horikawa H. Amagai M. T helper 17/T helper 22‒skewed inflammation with epidermal barrier dysfunction in nonmajor inherited ichthyosis subtypes.J Invest Dermatol. 2022; 142: 2303-2305Google Scholar). Although targeting disease-associated inflammation can help patients in some cases, there is a need for developing novel approaches for these skin disorders. Therefore, we asked the question: Would it be possible to restore DSG1 itself in SAM syndrome? We noted that the propeptide cleavage site downstream of the signal sequence mutation in the trafficking-deficient SAM mutant is not affected by the mutation. We reasoned that the small pool of mutant DSG1 that successfully enters the endoplasmic reticulum should be processed correctly in the Golgi, resulting in mature DSG1. Thus, if there were a way to improve the trafficking of the otherwise wild-type DSG1 to the plasma membrane, perhaps the SAM-mutant function could be restored. Given that DSG1 is recycled to the plasma membrane through the retromer, we investigated whether the retromer-enhancing chaperone, R55, could improve the membrane localization of wild-type DSG1 and the trafficking-deficient SAM mutant. Indeed, R55 brought the level of the SAM mutant at the cell surface up to that exhibited by wild-type DSG1, enhancing its ability to promote stratification. Furthermore, in vivo studies showed that R55 increased DSG1 on the cell surface of mouse epidermal KCs. These studies raise the possibility that the retromer could be exploited therapeutically to enhance the delivery and function of DSG1 in promoting differentiation and tissue integrity. Compared with the brain, the skin provides an attractive target for the therapeutic use of retromer chaperones owing to its accessibility, which circumvents the need for the compound to pass the blood−brain barrier and target the correct neurons without systemic toxicity. A potential caveat to using retromer chaperones for skin disease is that we do not yet know what other cargos and associated pathways exist in the epidermis or how their function could be affected by chaperone treatment. One epidermal transmembrane protein previously shown to be regulated by the retromer in other cell contexts is the glucose transporter GLUT1, an important regulator of glucose metabolism that is primarily restricted to basal layers in normal epidermis. Interestingly, as reported in the study by Hegazy et al., 2022aHegazy M. Koetsier J.L. Huffine A.L. Broussard J.A. Godsel B.M. Cohen-Barak E. et al.Epidermal stratification requires retromer-mediated desmoglein-1 recycling.Dev Cell. 2022; 57: 2683-2698.e8Google Scholar, we found that GLUT1 exhibited an increased association with the retromer, and its expression expanded into the superficial layers of DSG1-depleted mouse epidermis and skin from patients with SAM (Figure 1b). Our data suggest that this increase is due to the loss of the competing cargo DSG1 freeing up retromer components for GLUT1. Thus, the expression of the retromer cargo DSG1 at the onset of differentiation regulates the pools of retromer machinery available for regulating a protein critical for epidermal metabolic functions. Interestingly, although GLUT1 is upregulated in the skin of patients with psoriasis, DSG1 is downregulated in lesional psoriatic skin. Increased GLUT1 expression has been reported to contribute to psoriasiform hyperplasia, whereas loss of DSG1 has been shown to increase psoriasis-associated Th17 inflammatory signaling (Godsel et al., 2022Godsel L.M. Roth-Carter Q.R. Koetsier J.L. Tsoi L.C. Huffine A.L. Broussard J.A. et al.Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor.J Clin Invest. 2022; 132e144363Google Scholar; Zhang et al., 2018Zhang Z. Zi Z. Lee E.E. Zhao J. Contreras D.C. South A.P. et al.Differential glucose requirement in skin homeostasis and injury identifies a therapeutic target for psoriasis.Nat Med. 2018; 24: 617-627Google Scholar). The importance of this reciprocal pattern of DSG1 and GLUT1 expression in epidermal disorders has not been explored, but together, these observations expose potential links between DSG1 deficiency, epidermal metabolism, and inflammation. They also highlight the challenge of using retromer chaperones as a therapeutic intervention. It is unclear whether retromer chaperone−mediated enhancement of DSG1 is sufficient to dampen the pathological effect of GLUT1 increases. Further studies are necessary to determine how drug treatment affects the balance of different cargos and the extent to which cargo imbalances contribute to disease pathogenesis. More broadly, we also need a better handle on what other retromer cargo may be present in the epidermis and what pathways they regulate to maintain epidermal homeostasis. Considering that the retromer can form distinct complexes with accessory proteins that regulate cargo specificity, one approach to increasing the selectivity of retromer therapeutics for specific cargo could be to target these modulators. Thus, studies aimed at comprehensively identifying and characterizing both the landscape of epidermal retromer cargos and associated retromer complexes are warranted to further assess the potential of retromer chaperones in the treatment of skin disease. In considering the use of retromer chaperones for skin disorders, it is interesting to note several poorly understood observations that link neuronal and skin biology. In one instance, patients with Parkinson’s disease have a higher risk of developing melanoma. Although the pathomechanism of Parkinson’s disease−associated melanoma is not well-understood, the Parkinson’s disease−associated genes parkin and alpha-synuclein, both of which have been shown to modulate retromer-dependent trafficking, have also been implicated in melanoma (Ye et al., 2020Ye Q. Wen Y. Al-Kuwari N. Chen X. Association between Parkinson's disease and melanoma: putting the pieces together.Front Aging Neurosci. 2020; 12: 60Google Scholar). Alzheimer’s disease and psoriasis have also been linked through shared inflammatory pathways involving IL-12 and IL-23 (Zhang et al., 2021Zhang H. Zhang D. Tang K. Sun Q. The relationship between Alzheimer's disease and skin diseases: a review.Clin Cosmet Investig Dermatol. 2021; 14: 1551-1560Google Scholar). Studies testing the importance of retromer-mediated trafficking in nonneuronal tissues could also pave the way for the use of retromer chaperones more broadly for human disease and reveal additional strategies directed toward increasing the expression or decreasing the degradation of retromer components. The authors state no conflict of interest. The authors would like to thank Gregory Petsko, Andrew Kowalczyk, and Quinn Roth-Carter for helpful discussion and feedback. Work by the authors is supported by National Institutes of Health grants R01 AR043380, R01 AR041836, and CA228196; the Leo Foundation Award and the Joseph L. Mayberry Endowment (KJG); and T32 CA009560 and F31 AR076188 (MH).
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