REG1A explained

Pancreatic Stone Protein (PSP), also known as Lithostathine-1-alpha islet cells regeneration factor (ICRF) or islet of Langerhans regenerating protein (REG) is a protein that in humans is encoded by the REG1A gene as a single polypeptide of 144 amino acids further cleaved by trypsin to produce a 133 amino acid protein that is O-linked glycosylated on threonine 27. This protein is a type I subclass member of the Regenerating protein family. The Reg protein family is a multi protein family grouped into four subclasses, types I, II, III and IV based on the primary structures of the proteins.^{[1] [2] [3]} Reg family members REG1B, REGL, PAP and this gene are tandemly clustered on chromosome 2p12 and may have arisen from the same ancestral gene by gene duplication.The PSP is mostly produced in Human by the acinar cells of the pancreas and is secreted in the duodenum by the same pathway that pancreatic exocrine enzymes. It has C-terminal C-type lectin domain whose binding partner is currently unknown.

Function

Pancreas development and regeneration

The PSP has been shown to be associated with islet cell regeneration and diabetogenesis and may be involved in pancreatic lithogenesis (creation of pancreatic stones; pancreatic calculi).

Sepsis

The blood PSP concentration has been shown to increase substantially in response to a sepsis event. Consequently, the use of the PSP as a biomarker of sepsis has been investigated thoroughly and the result of these researches confirmed the high diagnostic accuracy of the PSP for sepsis.^[4] Of particular interest, PSP concentration has been shown to increase early in the development of a septic event, as illustrated in a cohort of severely burnt patients ^[5]

Further reading

• De Reggi M, Gharib B . Protein-X, Pancreatic Stone-, Pancreatic thread-, reg-protein, P19, lithostathine, and now what? Characterization, structural analysis and putative function(s) of the major non-enzymatic protein of pancreatic secretions . Curr. Protein Pept. Sci. . 2 . 1 . 19–42 . 2002 . 12369899 . 10.2174/1389203013381233 .
• Itoh T, Tsuzuki H, Katoh T, Teraoka H, Matsumoto K, Yoshida N, Terazono K, Watanabe T, Yonekura H, Yamamoto H . Isolation and characterization of human reg protein produced in Saccharomyces cerevisiae . FEBS Lett. . 272 . 1–2 . 85–8 . 1990 . 2226837 . 10.1016/0014-5793(90)80454-Q . 31078322 . free .
• de la Monte SM, Ozturk M, Wands JR . Enhanced expression of an exocrine pancreatic protein in Alzheimer's disease and the developing human brain . J. Clin. Invest. . 86 . 3 . 1004–13 . 1990 . 2394826 . 296822 . 10.1172/JCI114762 .
• De Caro AM, Adrich Z, Fournet B, Capon C, Bonicel JJ, De Caro JD, Rovery M . N-terminal sequence extension in the glycosylated forms of human pancreatic stone protein. The 5-oxoproline N-terminal chain is O-glycosylated on the 5th amino acid residue . Biochim. Biophys. Acta . 994 . 3 . 281–4 . 1989 . 2493268 . 10.1016/0167-4838(89)90305-1 .
• Giorgi D, Bernard JP, Rouquier S, Iovanna J, Sarles H, Dagorn JC . Secretory pancreatic stone protein messenger RNA. Nucleotide sequence and expression in chronic calcifying pancreatitis . J. Clin. Invest. . 84 . 1 . 100–6 . 1989 . 2525567 . 303958 . 10.1172/JCI114128 .
• Stewart TA . The human reg gene encodes pancreatic stone protein . Biochem. J. . 260 . 2 . 622–3 . 1989 . 2764894 . 1138718 . 10.1042/bj2600622.
• Terazono K, Yamamoto H, Takasawa S, Shiga K, Yonemura Y, Tochino Y, Okamoto H . A novel gene activated in regenerating islets . J. Biol. Chem. . 263 . 5 . 2111–4 . 1988 . 10.1016/S0021-9258(18)69176-8 . 2963000 . free .
• Rouimi P, Bonicel J, Rovery M, De Caro A . Cleavage of the Arg-Ile bond in the native polypeptide chain of human pancreatic stone protein . FEBS Lett. . 216 . 2 . 195–9 . 1987 . 3108036 . 10.1016/0014-5793(87)80688-9 . 37809879 .
• Rouimi P, de Caro J, Bonicel J, Rovery M, de Caro A . The disulfide bridges of the immunoreactive forms of human pancreatic stone protein isolated from pancreatic juice . FEBS Lett. . 229 . 1 . 171–4 . 1988 . 3345835 . 10.1016/0014-5793(88)80820-2 . 24682537 . free .
• Montalto G, Bonicel J, Multigner L, Rovery M, Sarles H, De Caro A . Partial amino acid sequence of human pancreatic stone protein, a novel pancreatic secretory protein . Biochem. J. . 238 . 1 . 227–32 . 1987 . 3541906 . 1147119 . 10.1042/bj2380227.
• De Caro AM, Bonicel JJ, Rouimi P, De Caro JD, Sarles H, Rovery M . Complete amino acid sequence of an immunoreactive form of human pancreatic stone protein isolated from pancreatic juice . Eur. J. Biochem. . 168 . 1 . 201–7 . 1987 . 3665916 . 10.1111/j.1432-1033.1987.tb13405.x .
• Gross J, Carlson RI, Brauer AW, Margolies MN, Warshaw AL, Wands JR . Isolation, characterization, and distribution of an unusual pancreatic human secretory protein . J. Clin. Invest. . 76 . 6 . 2115–26 . 1986 . 3908481 . 424321 . 10.1172/JCI112216 .
• Perfetti R, Hawkins AL, Griffin CA, Egan JM, Zenilman ME, Shuldiner AR . Assignment of the human pancreatic regenerating (REG) gene to chromosome 2p12 . Genomics . 20 . 2 . 305–7 . 1994 . 8020983 . 10.1006/geno.1994.1173 . free .
• Otonkoski T, Mally MI, Hayek A . Opposite effects of beta-cell differentiation and growth on reg expression in human fetal pancreatic cells . Diabetes . 43 . 9 . 1164–6 . 1994 . 8070617 . 10.2337/diabetes.43.9.1164 .
• Moriizumi S, Watanabe T, Unno M, Nakagawara K, Suzuki Y, Miyashita H, Yonekura H, Okamoto H . Isolation, structural determination and expression of a novel reg gene, human regI beta . Biochim. Biophys. Acta . 1217 . 2 . 199–202 . 1994 . 8110835 . 10.1016/0167-4781(94)90035-3 .
• Bartoli C, Gharib B, Giorgi D, Sansonetti A, Dagorn JC, Bergé-Lefranc JL . A gene homologous to the reg gene is expressed in the human pancreas . FEBS Lett. . 327 . 3 . 289–93 . 1993 . 8348956 . 10.1016/0014-5793(93)81006-L . 44565895 .
• Bertrand JA, Pignol D, Bernard JP, Verdier JM, Dagorn JC, Fontecilla-Camps JC . Crystal structure of human lithostathine, the pancreatic inhibitor of stone formation . EMBO J. . 15 . 11 . 2678–84 . 1996 . 8654365 . 450203 . 10.1002/j.1460-2075.1996.tb00628.x.
• Patard L, Stoven V, Gharib B, Bontems F, Lallemand JY, De Reggi M . What function for human lithostathine?: structural investigations by three-dimensional structure modeling and high-resolution NMR spectroscopy . Protein Eng. . 9 . 11 . 949–57 . 1997 . 8961348 . 10.1093/protein/9.11.949 . free .

Notes and References

1. Watanabe T, Yonekura H, Terazono K, Yamamoto H, Okamoto H . Complete nucleotide sequence of human reg gene and its expression in normal and tumoral tissues. The gene encode protein, pancreatic stone protein, and pancreatic thread protein are one and the same product of the gene . J Biol Chem . 265 . 13 . 7432–9 . Jun 1990 . 10.1016/S0021-9258(19)39132-X . 2332435 . free .
2. Gharib B, Fox MF, Bartoli C, Giorgi D, Sansonetti A, Swallow DM, Dagorn JC, Berge-lefranc JL . Human regeneration protein/lithostathine genes map to chromosome 2p12 . Ann Hum Genet . 57 . Pt 1 . 9–16 . Aug 1993 . 8333731 . 10.1111/j.1469-1809.1993.tb00882.x . 19794817 .
3. Web site: Entrez Gene: REG1A regenerating islet-derived 1 alpha (pancreatic stone protein, pancreatic thread protein).
4. Eggimann P, Que YA, Rebeaud F . Measurement of pancreatic stone protein in the identification and management of sepsis . Biomark Med . 12 . 2 . 135–145 . Jan 2019 . 30672312 . 10.2217/bmm-2018-0194 . free .
5. Klein HJ, Niggemann P, Buehler PK, Lehner F, Schweizer R, Rittirsch D, Fuchs N, Waldner M, Steiger P, Giovanoli P, Reding T, Graf R, Plock JA . Pancreatic Stone Protein Predicts Sepsis in Severely Burned Patients Irrespective of Trauma Severity: A Monocentric Observational Study . Ann Surg . Jan 2020 . 274 . 6 . e1179–e1186 . 31972652 . 10.1097/SLA.0000000000003784. 210882608 .