Four Decades After the Discovery of Regenerating Islet-Derived (Reg) Proteins: Current Understanding and Challenges

Abstract

Regenerating islet-derived (Reg) proteins have emerged as multifunctional agents with pro-proliferative, anti-apoptotic, differentiation-inducing and bactericidal properties. Over the last 40 years since first discovered, Reg proteins have been implicated in a gamut of maladies including diabetes, various types of cancer of the digestive tract, and Alzheimer disease. Surprisingly though, a consensus is still absent on the regulation of their expression, and molecular underpinning of their function. Here, we provide a critical appraisal of recent findings in the field of Reg protein biology. Specifically, the structural characteristics are reviewed particularly in connection with established or purported functions of different members of the Reg family. Moreover, Reg expression patterns in different tissues both under normal and pathophysiological conditions are summarized. Putative receptors and cascades reported to relay Reg signaling inciting cellular responses are presented aiming at a better appreciation of the biological activities of the distinct Reg moieties. Challenges are also discussed that have hampered thus far the rapid progress in this field such as the use of non-standard nomenclature for Reg molecules among various research groups, the existence of multiple Reg members with significant degree of homology and possibly compensatory modes of action, and the need for common assays with robust readouts of Reg activity. Coordinated research is warranted going forward, given that several research groups have independently linked Reg proteins to diseased states and raised the possibility that these biomolecules can serve as therapeutic targets and biomarkers.

Keywords: Reg proteins; diabetes; gastrointestinal cancer; pancreas; pancreatic adenocarcinoma.

FIGURE 1

Amino acid sequence homology of the (A) human vs. the mouse Reg proteins, (B) human, and (C) mouse Reg proteins to each other. The numbers in parentheses refer to the individual protein entry ID in the UniProt database (http://www.uniprot.org). When multiple IDs are available for a protein, an ID is selected corresponding to an entry that has undergone review. Homology between sequences was quantified with the NCBI protein BLAST tool (https://blast.ncbi.nlm.nih.gov).

FIGURE 2

Protein structures obtained from the Protein Data Bank (PDB: https://www.rcsb.org/) are shown in figures of ribbon and ball and stick (colored by residues) of the human (A) REG1A (PDB ID: 1QDD, Gerbaud et al., 2000), (B) REG3A (PDB ID: 4MTH, Mukherjee et al., 2014), and (C) REG4 (PDB ID: 2KV3, Ho et al., 2010). In REG1A, the signal peptide is 22-aa long shortening the protein chain from 166 to 144 aa with a trypsin-sensitive arginine at position 11 (R-11) (De Reggi and Gharib, 2001). A Thr5-O-linked glycan is also featured that gives rise to different isoforms (De Reggi et al., 1995). REG3A (HIP/PAP) recognizes peptidoglycan carbohydrate backbones through an 114-EPN-116 motif that confers bactericidal activity while a E114Q mutation weakens this interaction (Lehotzky et al., 2010). REG4 has a C-type like domain (CTLD) and two calcium-independent sites that bind mannan (Ho et al., 2010). Images were created in LiteMol Suite (Sehnal et al., 2017).