Microproteins: Overlooked regulators of physiology and disease

Summary: Ongoing efforts to generate a complete and accurate annotation of the genome have revealed a significant blind spot for small proteins (<100 amino acids) originating from short open reading frames (sORFs). The recent discovery of numerous sORF-encoded proteins, termed microproteins, that play diverse roles in critical cellular processes has ignited the field of microprotein biology. Large-scale efforts are currently underway to identify sORF-encoded microproteins in diverse cell-types and tissues and specialized methods and tools have been developed to aid in their discovery, validation, and functional characterization. Microproteins that have been identified thus far play important roles in fundamental processes including ion transport, oxidative phosphorylation, and stress signaling. In this review, we discuss the optimized tools available for microprotein discovery and validation, summarize the biological functions of numerous microproteins, outline the promise for developing microproteins as therapeutic targets, and look forward to the future of the field of microprotein biology

Bone Morphogenetic Protein Signaling Is Required for Aortic Valve Calcification

OBJECTIVE: Calcific aortic valve disease (CAVD) is the most prevalent type of heart valve disease, affecting ≈2% of the US population. CAVD is characterized by the presence of calcific nodules, resulting in aortic valve (AoV) stenosis; however, the underlying mechanisms driving disease remain unknown. Studies of human diseased AoV provide initial evidence that bone morphogenetic protein (BMP) signaling, essential for normal bone formation, is activated during CAVD. Mice deficient in Klotho, an FGF23 transmembrane coreceptor, exhibit premature aging and develop AoV calcific nodules as occurs in human CAVD. The role of BMP signaling in the development of CAVD was examined in porcine aortic valve interstitial cells (VICs) and Klotho(-/-) mice. APPROACH AND RESULTS: We show that activation of BMP signaling, as indicated by pSmad1/5/8 expression, precedes and later localizes with AoV calcification in Klotho(-/-) mice. In addition, cellular and extracellular matrix changes resembling features of normal bone formation are accompanied by increased osteochondrogenic gene induction in calcified Klotho(-/-) AoV. Likewise, osteogenic media treatment of porcine VICs results in BMP pathway activation, increased osteochondrogenic gene induction, and formation of calcific nodules in vitro. We demonstrate that genetic inactivation of the BMP type IA receptor in Klotho(-/-) aortic VICs, as well as BMP pathway inhibition of osteogenic media-treated aortic VICs in vitro, results in the inhibition of AoV calcification. CONCLUSIONS: BMP signaling and osteochondrogenic gene induction are active in calcified Klotho(-/-) AoV in vivo and calcified porcine aortic VICs in vitro. Importantly, BMP signaling is required for the development of AoV calcification in vitro and in vivo