Serum amyloid A1

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Serum amyloid A1 (SAA1) is a protein that in humans is encoded by the SAA1 gene.[1][2][3] SAA1 is a major acute-phase protein mainly produced by hepatocytes in response to infection, tissue injury and malignancy.[4] When released into blood circulation, SAA1 is present as an apolipoprotein associated with high-density lipoprotein (HDL).[5] SAA1 is a major precursor of amyloid A (AA), the deposit of which leads to inflammatory amyloidosis.[6][7]

Gene

The gene coding for human SAA1 is one of the 4 SAA genes mapped to a region in the short arm on Chromosome 15.[8] Two of these genes, SAA1 and SAA2, are inducible during acute-phase response, whereas SAA3 is a pseudogene in humans[9] and SAA4 is constitutively expressed in a variety of tissues and cells. Single nucleotide polymorphisms (SNPs) are found in SAA1 in both coding and non-coding sequences, with those located in the coding sequence defining 5 isoforms of SAA1 (SAA1.1 – 1.5). Genetic studies have shown association of some of these SNPs with the disposition to several human diseases including familiar Mediterranean fever, coronary artery diseases, cerebral infarction, and osteoporosis. Mice also have 4 Saa genes. A major difference between human and mouse SAA genes is the expression of the mouse Saa3 gene for a functional protein, generally considered an inducible SAA in inflammatory tissues.

Protein structure

The product of human SAA1 is a pre-protein of 122 amino acids, with a cleavable signal peptide of 18 amino acids. Mature SAA1 consists of 104 amino acids with an apparent molecular weight of 12,500. A crystal structure of SAA1.1 has been solved recently (Figure 1). Native SAA1 is a hexamer with each subunit assuming an antiparallel 4-helix bundle structure.[10] The structure is cone-shaped with its apex forming a binding site for HDL and heparin. The N-terminal helices 1 and 3 have been identified as amyloidogenic peptides of SAA1.1, that are not presence on protein surface in native SAA1 protein. These findings provide the structural basis for the formation of amyloid A fibrils. The human SAA1.1 is comparable at the subunit level with the recently solved structure of mouse Saa3.[11]

Inducible expression

SAA1 and SAA2 are highly inducible and hence called acute-phase SAA. Inflammatory cytokines such as IL-1β, IL-6 and TNF-α are major stimulants for hepatocyte expression of the SAA1 gene.[12] Inducible expression of the acute-phase SAA genes is mainly regulated at the transcription level and involves the transcription factors C/EBP, NF-κB, AP2, SAF, Sp1 and STAT3. Elevation of the transcript of SAA1 is often seen in cDNA arrays used for detection of proinflammatory cytokine expression. SAA1 protein level correlates with its transcript level, and has long been considered a clinical indicator for inflammatory conditions.

Interactions

In addition to its association with HDL, SAA1 interacts with a number of mammalian proteins, mostly cell surface proteins such as receptors. SAA1 binding to the αvβ3 integrin produces an inhibitory effect on the growth of nasopharyngeal carcinoma.[13] Several receptors for SAA1 have been identified using an SAA1 hybrid protein containing two amino acid substitutions from SAA2.[14] These receptors include the G protein-coupled chemoattractant receptor FPR2 (formyl peptide receptor 2),[15] believed to mediate the chemotactic activity of the recombinant SAA1; the murine scavenger receptor SR-BI [16] and the human equivalent CLA-1.,[17] for a possible role in SAA1-dependent cholesterol metabolism. Moreover, the Toll-like receptors TLR2[18] and TLR4[19] mediate SAA1-induced cytokine gene expression. The P2X7 purinergic receptor is another receptor used by SAA1 for a number of cellular functions including the activation of NLRP3 inflammasomes.[20]

SAA1 has been found to interact with outer membrane protein A (ompA) of several Gram-negative bacteria including E. coli, Salmonella typhimurium, Shigella flexneri, Vibrio cholerae and P. aeruginosa.[21] Exposure of these Gram-negative bacteria to SAA1 promotes uptake of the bacteria by neutrophils, suggesting that SAA1 serves as an opsonin that enhances bacteria clearance.[22] A more recent study identified SAA1 interaction with retinol, resulting in reduced bacterial burden.[23] These findings suggest that SAA1 has a function in host defense against bacterial infection.

Functions and clinical relevance

The biological function of SAA1 has not been fully understood despite intensive research in the last three decades. Research tools such as the SAA1 knockout mice and transgenic mice have become available only recently. It has been well established, however, that elevated plasma concentration of SAA1 is associated with a multitude of inflammatory conditions. As a result, SAA1 has been a clinical indicator and reliable biomarker for inflammatory diseases, chronic metabolic disorders and late-stage malignancy.[24] Inflammatory amyloidosis results from chronic inflammation with increased production of SAA1, which is a major precursor of amyloid A fibril deposit in various tissues.[25]

SAA1 has been extensively studied for its binding to HDL, with results suggesting a role in lipid metabolism. During the acute-phase response, elevated levels of SAA1 in the plasma displaces ApoA-I and becomes a major apolipoprotein of HDL.[26] The exact biological consequence of HDL remodeling by SAA1 is still under investigation, using recently developed tools such as the Saa1 and Saa2 knockout mice. SAA1 is also believed to contribute to the development of atherosclerosis.[27][28] However, in an ApoE-deficient mouse model, deletion of the Saa1/Saa2 genes does not appear to affect atherosclerotic lesions.[29]

Ex vivo and in vitro studies have shown that the recombinant human SAA1 hybrid protein has strong chemotactic activity for neutrophils and macrophages.[30] This effect is believed to be mediated through FPR2, a G protein-coupled chemoattractant receptor.[31] The same receptor also mediates the cytokine-like activity of the recombinant SAA1, resulting in an elevated expression of IL-8 in neutrophils.[32] The recombinant SAA1 has been reported to induce the expression of a variety of inflammatory cytokines including IL-1β, TNF-α, IL-6, IL-12p40,[33][34] as well as immunoregulatory cytokines such as IL-23,[35] IL-33[36] and growth-stimulatory cytokines such as G-CSF.[37]

SAA1 may also be produced by macrophages and epithelial cells in various tissues. It has been shown to promote local Th17 response in the gut.[38] This finding, which is based on both Saa1/Saa2 knockout mice and ex vivo studies of T cells, strongly suggest a local immunomodulatory function of SAA1 as opposed to its established role as an acute-phase protein produced in the liver and present in the plasma as an apolipoprotein of HDL. Transgenic expression of human SAA1.1 in mouse liver aggravates T cell-mediated hepatitis through elevated production of chemokines,[39] which involves the SAA1 receptor TLR2. Secretion of SAA1 by melanoma cells may induce anti-inflammatory IL-10-secreting neutrophils that interact with invariant natural killer T cells (iNKT cells).[40] In addition, SAA1 can skew macrophages to a M2 phenotype.[41]

Published reports link SAA1 to a number of malignancies, but a causal relationship has not been established. SAA1 has been associated with tumor pathogenesis,[42] and its gene polymorphism is a contributing factor to certain types of malignant tumors.[43] SAA1 has also been shown to affect the tumor microenvironment and contribute to tumor cell metastasis.[44]

Some of the results obtained with the recombinant human SAA1 hybrid remain controversial, as the protein does not have exactly the same sequence of human SAA1 and its properties may be different from the native SAA1.[45] Other studies have shown that native human SAA1 retains some of the cytokine-like activities such as the G-CSF-induction capability[46]

Recent studies using the Saa1/Saa2 knockout mice showed weakened Th17 response in gut epithelial cells,[47] suggesting that SAA1 plays a role in vivo in the regulation of immunity.

Notes


References

  1. ↑ Glaser T, Housman D, Lewis WH, Gerhard D, Jones C (Nov 1989). "A fine-structure deletion map of human chromosome 11p: analysis of J1 series hybrids". Somatic Cell and Molecular Genetics. 15 (6): 477–501. doi:10.1007/BF01534910. PMID 2595451.
  2. ↑ Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B (Sep 1997). "A model for p53-induced apoptosis". Nature. 389 (6648): 300–5. doi:10.1038/38525. PMID 9305847.
  3. ↑ "Entrez Gene: SAA1 serum amyloid A1".
  4. ↑ Gabay C, Kushner I (Feb 1999). "Acute-phase proteins and other systemic responses to inflammation". The New England Journal of Medicine. 340 (6): 448–54. doi:10.1056/NEJM199902113400607. PMID 9971870.
  5. ↑ Benditt EP, Eriksen N (Sep 1977). "Amyloid protein SAA is associated with high density lipoprotein from human serum". Proceedings of the National Academy of Sciences of the United States of America. 74 (9): 4025–8. doi:10.1073/pnas.74.9.4025. PMC 431828. PMID 198813.
  6. ↑ Husebekk A, Skogen B, Husby G, Marhaug G (Mar 1985). "Transformation of amyloid precursor SAA to protein AA and incorporation in amyloid fibrils in vivo". Scandinavian Journal of Immunology. 21 (3): 283–7. doi:10.1111/j.1365-3083.1985.tb01431.x. PMID 3922050.
  7. ↑ Tape C, Tan R, Nesheim M, Kisilevsky R (Sep 1988). "Direct evidence for circulating apoSAA as the precursor of tissue AA amyloid deposits". Scandinavian Journal of Immunology. 28 (3): 317–24. doi:10.1111/j.1365-3083.1988.tb01455.x. PMID 3194701.
  8. ↑ Uhlar CM, Burgess CJ, Sharp PM, Whitehead AS (Jan 1994). "Evolution of the serum amyloid A (SAA) protein superfamily". Genomics. 19 (2): 228–35. doi:10.1006/geno.1994.1052. PMID 8188253.
  9. ↑ Kluve-Beckerman B, Drumm ML, Benson MD (Nov 1991). "Nonexpression of the human serum amyloid A three (SAA3) gene". DNA and Cell Biology. 10 (9): 651–61. doi:10.1089/dna.1991.10.651. PMID 1755958.
  10. ↑ Lu J, Yu Y, Zhu I, Cheng Y, Sun PD (Apr 2014). "Structural mechanism of serum amyloid A-mediated inflammatory amyloidosis". Proceedings of the National Academy of Sciences of the United States of America. 111 (14): 5189–94. doi:10.1073/pnas.1322357111. PMC 3986191. PMID 24706838.
  11. ↑ Derebe MG, Zlatkov CM, Gattu S, Ruhn KA, Vaishnava S, Diehl GE, MacMillan JB, Williams NS, Hooper LV (Jul 2014). "Serum amyloid A is a retinol binding protein that transports retinol during bacterial infection". eLife. 3: e03206. doi:10.7554/eLife.03206. PMC 4129439. PMID 25073702.
  12. ↑ Jensen LE, Whitehead AS (Sep 1998). "Regulation of serum amyloid A protein expression during the acute-phase response". The Biochemical Journal. 334 (3): 489–503. doi:10.1042/bj3340489. PMC 1219714. PMID 9729453.
  13. ↑ Lung HL, Man OY, Yeung MC, Ko JM, Cheung AK, Law EW, Yu Z, Shuen WH, Tung E, Chan SH, Bangarusamy DK, Cheng Y, Yang X, Kan R, Phoon Y, Chan KC, Chua D, Kwong DL, Lee AW, Ji MF, Lung ML (Feb 2015). "SAA1 polymorphisms are associated with variation in antiangiogenic and tumor-suppressive activities in nasopharyngeal carcinoma". Oncogene. 34 (7): 878–89. doi:10.1038/onc.2014.12. PMID 24608426.
  14. ↑ "Recombinant human Apo-SAA".
  15. ↑ Su SB, Gong W, Gao JL, Shen W, Murphy PM, Oppenheim JJ, Wang JM (Jan 1999). "A seven-transmembrane, G protein-coupled receptor, FPRL1, mediates the chemotactic activity of serum amyloid A for human phagocytic cells". The Journal of Experimental Medicine. 189 (2): 395–402. doi:10.1084/jem.189.2.395. PMC 2192984. PMID 9892621.
  16. ↑ Cai L, de Beer MC, de Beer FC, van der Westhuyzen DR (Jan 2005). "Serum amyloid A is a ligand for scavenger receptor class B type I and inhibits high density lipoprotein binding and selective lipid uptake". The Journal of Biological Chemistry. 280 (4): 2954–61. doi:10.1074/jbc.M411555200. PMID 15561721.
  17. ↑ Baranova IN, Vishnyakova TG, Bocharov AV, Kurlander R, Chen Z, Kimelman ML, Remaley AT, Csako G, Thomas F, Eggerman TL, Patterson AP (Mar 2005). "Serum amyloid A binding to CLA-1 (CD36 and LIMPII analogous-1) mediates serum amyloid A protein-induced activation of ERK1/2 and p38 mitogen-activated protein kinases". The Journal of Biological Chemistry. 280 (9): 8031–40. doi:10.1074/jbc.M405009200. PMID 15576377.
  18. ↑ Cheng N, He R, Tian J, Ye PP, Ye RD (Jul 2008). "Cutting edge: TLR2 is a functional receptor for acute-phase serum amyloid A". Journal of Immunology. 181 (1): 22–6. doi:10.4049/jimmunol.181.1.22. PMC 2464454. PMID 18566366.
  19. ↑ Sandri S, Rodriguez D, Gomes E, Monteiro HP, Russo M, Campa A (May 2008). "Is serum amyloid A an endogenous TLR4 agonist?". Journal of Leukocyte Biology. 83 (5): 1174–80. doi:10.1189/jlb.0407203. PMID 18252871.
  20. ↑ Niemi K, Teirilä L, Lappalainen J, Rajamäki K, Baumann MH, Öörni K, Wolff H, Kovanen PT, Matikainen S, Eklund KK (Jun 2011). "Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway". Journal of Immunology. 186 (11): 6119–28. doi:10.4049/jimmunol.1002843. PMID 21508263.
  21. ↑ Hari-Dass R, Shah C, Meyer DJ, Raynes JG (May 2005). "Serum amyloid A protein binds to outer membrane protein A of gram-negative bacteria". The Journal of Biological Chemistry. 280 (19): 18562–7. doi:10.1074/jbc.M500490200. PMID 15705572.
  22. ↑ Shah C, Hari-Dass R, Raynes JG (Sep 2006). "Serum amyloid A is an innate immune opsonin for Gram-negative bacteria". Blood. 108 (5): 1751–7. doi:10.1182/blood-2005-11-011932. PMID 16735604.
  23. ↑ Derebe MG, Zlatkov CM, Gattu S, Ruhn KA, Vaishnava S, Diehl GE, MacMillan JB, Williams NS, Hooper LV (29 July 2014). "Serum amyloid A is a retinol binding protein that transports retinol during bacterial infection". eLife. 3: e03206. doi:10.7554/eLife.03206. PMC 4129439. PMID 25073702.
  24. ↑ Malle E, Sodin-Semrl S, Kovacevic A (Jan 2009). "Serum amyloid A: an acute-phase protein involved in tumour pathogenesis". Cellular and Molecular Life Sciences. 66 (1): 9–26. doi:10.1007/s00018-008-8321-x. PMC 4864400. PMID 18726069.
  25. ↑ Tape C, Tan R, Nesheim M, Kisilevsky R (Sep 1988). "Direct evidence for circulating apoSAA as the precursor of tissue AA amyloid deposits". Scandinavian Journal of Immunology. 28 (3): 317–24. doi:10.1111/j.1365-3083.1988.tb01455.x. PMID 3194701.
  26. ↑ Kisilevsky R, Manley PN (Mar 2012). "Acute-phase serum amyloid A: perspectives on its physiological and pathological roles". Amyloid. 19 (1): 5–14. doi:10.3109/13506129.2011.654294. PMID 22320226.
  27. ↑ King VL, Thompson J, Tannock LR (Aug 2011). "Serum amyloid A in atherosclerosis". Current Opinion in Lipidology. 22 (4): 302–7. doi:10.1097/MOL.0b013e3283488c39. PMID 21734573.
  28. ↑ Thompson JC, Jayne C, Thompson J, Wilson PG, Yoder MH, Webb N, Tannock LR (Feb 2015). "A brief elevation of serum amyloid A is sufficient to increase atherosclerosis". Journal of Lipid Research. 56 (2): 286–93. doi:10.1194/jlr.M054015. PMC 4306683. PMID 25429103.
  29. ↑ De Beer MC, Wroblewski JM, Noffsinger VP, Rateri DL, Howatt DA, Balakrishnan A, Ji A, Shridas P, Thompson JC, van der Westhuyzen DR, Tannock LR, Daugherty A, Webb NR, De Beer FC (Feb 2014). "Deficiency of endogenous acute phase serum amyloid A does not affect atherosclerotic lesions in apolipoprotein E-deficient mice". Arteriosclerosis, Thrombosis, and Vascular Biology. 34 (2): 255–61. doi:10.1161/ATVBAHA.113.302247. PMC 3951741. PMID 24265416.
  30. ↑ Badolato R, Wang JM, Murphy WJ, Lloyd AR, Michiel DF, Bausserman LL, Kelvin DJ, Oppenheim JJ (Jul 1994). "Serum amyloid A is a chemoattractant: induction of migration, adhesion, and tissue infiltration of monocytes and polymorphonuclear leukocytes". The Journal of Experimental Medicine. 180 (1): 203–9. doi:10.1084/jem.180.1.203. PMC 2191543. PMID 7516407.
  31. ↑ Su SB, Gong W, Gao JL, Shen W, Murphy PM, Oppenheim JJ, Wang JM (Jan 1999). "A seven-transmembrane, G protein-coupled receptor, FPRL1, mediates the chemotactic activity of serum amyloid A for human phagocytic cells". The Journal of Experimental Medicine. 189 (2): 395–402. doi:10.1084/jem.189.2.395. PMC 2192984. PMID 9892621.
  32. ↑ He R, Sang H, Ye RD (Feb 2003). "Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1/LXA4R". Blood. 101 (4): 1572–81. doi:10.1182/blood-2002-05-1431. PMID 12393391.
  33. ↑ Patel H, Fellowes R, Coade S, Woo P (Oct 1998). "Human serum amyloid A has cytokine-like properties". Scandinavian Journal of Immunology. 48 (4): 410–8. doi:10.1046/j.1365-3083.1998.00394.x. PMID 9790312.
  34. ↑ Cheng N, He R, Tian J, Ye PP, Ye RD (Jul 2008). "Cutting edge: TLR2 is a functional receptor for acute-phase serum amyloid A". Journal of Immunology. 181 (1): 22–6. doi:10.4049/jimmunol.181.1.22. PMC 2464454. PMID 18566366.
  35. ↑ He R, Shepard LW, Chen J, Pan ZK, Ye RD (Sep 2006). "Serum amyloid A is an endogenous ligand that differentially induces IL-12 and IL-23". Journal of Immunology. 177 (6): 4072–9. doi:10.4049/jimmunol.177.6.4072. PMID 16951371.
  36. ↑ Sun L, Zhu Z, Cheng N, Yan Q, Ye RD (Jul 2014). "Serum amyloid A induces interleukin-33 expression through an IRF7-dependent pathway". European Journal of Immunology. 44 (7): 2153–64. doi:10.1002/eji.201344310. PMC 4118754. PMID 24777946.
  37. ↑ He RL, Zhou J, Hanson CZ, Chen J, Cheng N, Ye RD (Jan 2009). "Serum amyloid A induces G-CSF expression and neutrophilia via Toll-like receptor 2". Blood. 113 (2): 429–37. doi:10.1182/blood-2008-03-139923. PMC 2615655. PMID 18952897.
  38. ↑ Sano T, Huang W, Hall JA, Yang Y, Chen A, Gavzy SJ, Lee JY, Ziel JW, Miraldi ER, Domingos AI, Bonneau R, Littman DR (Oct 2015). "An IL-23R/IL-22 Circuit Regulates Epithelial Serum Amyloid A to Promote Local Effector Th17 Responses". Cell. 163 (2): 381–93. doi:10.1016/j.cell.2015.08.061. PMID 26411290.
  39. ↑ Ji YR, Kim HJ, Bae KB, Lee S, Kim MO, Ryoo ZY (May 2015). "Hepatic serum amyloid A1 aggravates T cell-mediated hepatitis by inducing chemokines via Toll-like receptor 2 in mice". The Journal of Biological Chemistry. 290 (20): 12804–11. doi:10.1074/jbc.M114.635763. PMC 4432296. PMID 25847238.
  40. ↑ De Santo C, Arscott R, Booth S, Karydis I, Jones M, Asher R, Salio M, Middleton M, Cerundolo V (Nov 2010). "Invariant NKT cells modulate the suppressive activity of IL-10-secreting neutrophils differentiated with serum amyloid A". Nature Immunology. 11 (11): 1039–46. doi:10.1038/ni.1942. PMC 3001335. PMID 20890286.
  41. ↑ Sun L, Zhou H, Zhu Z, Yan Q, Wang L, Liang Q, Ye RD (May 2015). "Ex vivo and in vitro effect of serum amyloid a in the induction of macrophage M2 markers and efferocytosis of apoptotic neutrophils". Journal of Immunology. 194 (10): 4891–900. doi:10.4049/jimmunol.1402164. PMC 4417396. PMID 25870242.
  42. ↑ Malle E, Sodin-Semrl S, Kovacevic A (Jan 2009). "Serum amyloid A: an acute-phase protein involved in tumour pathogenesis". Cellular and Molecular Life Sciences. 66 (1): 9–26. doi:10.1007/s00018-008-8321-x. PMC 4864400. PMID 18726069.
  43. ↑ Lung HL, Man OY, Yeung MC, Ko JM, Cheung AK, Law EW, Yu Z, Shuen WH, Tung E, Chan SH, Bangarusamy DK, Cheng Y, Yang X, Kan R, Phoon Y, Chan KC, Chua D, Kwong DL, Lee AW, Ji MF, Lung ML (Feb 2015). "SAA1 polymorphisms are associated with variation in antiangiogenic and tumor-suppressive activities in nasopharyngeal carcinoma". Oncogene. 34 (7): 878–89. doi:10.1038/onc.2014.12. PMID 24608426.
  44. ↑ Hansen MT, Forst B, Cremers N, Quagliata L, Ambartsumian N, Grum-Schwensen B, Klingelhöfer J, Abdul-Al A, Herrmann P, Osterland M, Stein U, Nielsen GH, Scherer PE, Lukanidin E, Sleeman JP, Grigorian M (Jan 2015). "A link between inflammation and metastasis: serum amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4". Oncogene. 34 (4): 424–35. doi:10.1038/onc.2013.568. PMID 24469032.
  45. ↑ Christenson K, Björkman L, Ahlin S, Olsson M, Sjöholm K, Karlsson A, Bylund J (2013). "Endogenous Acute Phase Serum Amyloid A Lacks Pro-Inflammatory Activity, Contrasting the Two Recombinant Variants That Activate Human Neutrophils through Different Receptors". Frontiers in Immunology. 4: 92. doi:10.3389/fimmu.2013.00092. PMC 3631709. PMID 23626589.
  46. ↑ Kim MH, de Beer MC, Wroblewski JM, Webb NR, de Beer FC (Feb 2013). "SAA does not induce cytokine production in physiological conditions". Cytokine. 61 (2): 506–12. doi:10.1016/j.cyto.2012.10.019. PMC 3616876. PMID 23165195.
  47. ↑ Sano T, Huang W, Hall JA, Yang Y, Chen A, Gavzy SJ, Lee JY, Ziel JW, Miraldi ER, Domingos AI, Bonneau R, Littman DR (Oct 2015). "An IL-23R/IL-22 Circuit Regulates Epithelial Serum Amyloid A to Promote Local Effector Th17 Responses". Cell. 163 (2): 381–93. doi:10.1016/j.cell.2015.08.061. PMID 26411290.

Further reading

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