New Insights into Protein Hydroxylation and Its Important Role in Human Diseases

Abstract

Protein hydroxylation is a post-translational modification catalyzed by 2-oxoglutarate-dependent dioxygenases. The hydroxylation modification can take place on various amino acids, including but not limited to proline, lysine, asparagine, aspartate and histidine. A classical example of this modification is hypoxia inducible factor alpha (HIF-α) prolyl hydroxylation, which affects HIF-α protein stability via the Von-Hippel Lindau (VHL) tumor suppressor pathway, a Cullin 2-based E3 ligase adaptor protein frequently mutated in kidney cancer. In addition to protein stability regulation, protein hydroxylation may influence other post-translational modifications or the kinase activity of the modified protein (such as Akt and DYRK1A/B). In other cases, protein hydroxylation may alter protein-protein interaction and its downstream signaling events in vivo (such as OTUB1, MAPK6 and eEF2K). In this review, we highlight the recently identified protein hydroxylation targets and their pathophysiological roles, especially in cancer settings. Better understanding of protein hydroxylation will help identify novel therapeutic targets and their regulation mechanisms to foster development of more effective treatment strategies for various human cancers.

PLOD3 promotes lung metastasis via regulation of STAT3

“…5d ). We confirmed that JAK activity upstream of STAT3 resulted in an overall downregulation of JAK1, whereas no effects were observed in the case of JAK2 (data not shown) 40 . In this context, these findings strongly suggest that PLOD3 knockdown effectively suppresses the constitutive activation of STAT3 in lung cancer cells.…”

“…Furthermore, hydroxylation of the monovalent protein can modulate protein stability, thus regulating STAT3-Y705 phosphorylation by reducing JAK1 stability upon PLOD3 inhibition. In addition, hydroxylation can modulate the protein–protein interactions, thereby regulating STAT3 phosphorylation by regulating the binding of STAT3 to its corresponding kinase 40 . Hence, it is anticipated that hydroxylation regulates STAT3 phosphorylation via STAT3 and PLOD3 in the complex by binding in the cytoplasm.…”

Differences in Tolerance to Hypoxia: Physiological, Biochemical, and Molecular-Biological Characteristics

“…This triggers their identification by the E3 ubiquitin ligase complex, formed by von Hippel–Lindau tumor suppressor protein (pVHL), Cullin 2, elongin B and C, and RING-box 1 proteins. The hydroxylation happens thanks to PHDs reliant on oxygen, α-ketoglutarate, iron (Fe 2+ ), and vitamin C [ 32 , 33 , 34 ]. Despite the fact that all PHDs are expressed ubiquitously, they demonstrate tissue-specific differences in expression levels.…”

Current Trends in the Analysis of Post-translational Modifications

“…Although hydroxylation can take place on several amino acids including lysine, histidine, asparagine, aspartate, and aromatic residues, the most commonly hydroxylated amino acid is proline, which makes up almost one-third of collagen protein [110][111][112]. Hydroxylation generally takes place at the γ-C atom, yielding 4-hydroxyproline (4-Hyp), which has the ability to stabilize the secondary structure of the protein by the powerful electronegative effect of the hydroxy group [112].…”