Small Proline-Rich Protein 2A and 2D Are Regulated by the RBM38-p73 Axis and Associated with p73-Dependent Suppression of Chronic Inflammation

SIMPLE SUMMARY: Small proline-rich protein 2A and 2D (SPRR2A and SPRR2D) are structure proteins of cornified cell envelopes and function as a protective barrier against diverse external insults. However, the role of SPRR2A/2D in chronic inflammation remains unclear. Here, we showed that SPRR2A/2D expression is controlled by a regulatory loop formed by RNA-binding protein RBM38 and tumor suppressor p73. We also found that RBM38-mediated expression of SPRR2A/2D was p73-dependent and that induction of SPRR2A/2D during keratinocyte differentiation was dependent on both p73 and Rbm38. Furthermore, We found that Rbm38(−/−);Trp73(+/−) mice exhibited weak expression of SPRR2A/2D in multiple tissues and were susceptible to systemic chronic inflammation. Together, our data reveal that SPRR2A/2D are novel targets of the RBM38-p73 loop and contribute to p73-dependent suppression of chronic inflammation. ABSTRACT: Small proline-rich protein 2A and 2D (SPRR2A and SPRR2D) provide barrier function in terminally differentiated stratified squamous epithelia through the epidermal differentiation complex. However, little is known how SPRR2A/2D expression is controlled and their role in chronic inflammation. Here, we showed that that SPRR2A/2D expression is controlled by a regulatory loop formed by RNA-binding protein RBM38 and tumor suppressor p73. Specifically, we found that SPRR2A/2D expression was induced by ectopic expression of RBM38 or p73 but suppressed by knockout of Rbm38 or p73. We also found that RBM38-mediated expression of SPRR2A/2D was p73-dependent and that induction of SPRR2A/2D during keratinocyte differentiation was dependent on both p73 and Rbm38. Additionally, we found that SPRR2A/2D expression was closely associated with p73 expression in normal and cancerous tissues. To determine the biological function of the RBM38-p73 loop potentially via SPRR2A/2D, we generated a cohort of wild-type, Rbm38(−/−), Trp73(+/−), and Rbm38(−/−);Trp73(+/−) mice. We found that Rbm38(−/−);Trp73(+/−) mice had a much shorter lifespan than that for Rbm38(−/−)—and to a lesser extent for Trp73(+/−) mice—but were less prone to spontaneous tumors than Trp73(+/−) or Rbm38(−/−) mice. We also found that Rbm38(−/−);Trp73(+/−) mice exhibited weak expression of SPRR2A/2D in multiple tissues and were susceptible to systemic chronic inflammation, suggesting that decreased SPRR2A/2D expression is likely responsible for chronic inflammation in Rbm38(−/−);Trp73(+/−) mice, leading to a shortened lifespan. Together, our data reveal that SPRR2A/2D are novel targets of the RBM38-p73 loop and contribute to p73-dependent suppression of chronic inflammation.