YWHAZ explained

14-3-3 protein zeta/delta (14-3-3ζ) is a protein that in humans is encoded by the YWHAZ gene on chromosome 8.[1] [2] The protein encoded by this gene is a member of the 14-3-3 protein family and a central hub protein for many signal transduction pathways.[2] [3] 14-3-3ζ is a major regulator of apoptotic pathways critical to cell survival and plays a key role in a number of cancers and neurodegenerative diseases.[3] [4] [5] [6] [7]

Structure

14-3-3 proteins generally form ~30 kDa-long homo- or heterodimers.[8] [9] Each of the monomers are composed of 9 antiparallel alpha helices. Four alpha-helices (αC, αE, αG, and αI) form an amphipathic groove that serves as the ligand binding site, which can recognize three types of consensus binding motifs: RXX(pS/pT)XP, RXXX(pS/pT)XP, and (pS/pT)X1-2-COOH (where pS/pT represents phosphorylated serine/threonine). In addition to these primary interactions, the target protein can also bind outside the groove via secondary interactions.In particular, the crystallized structure of 14-3-3ζ forms a cup-shaped dimer when complexed with CBY.[9] The YWHAZ gene encodes two transcript variants which differ in the 5' UTR but produce the same protein.[2]

Function

14-3-3ζ is one of 7 members of the 14-3-3 protein family, which is ubiquitously expressed and highly conserved among plants and mammals.[2] [3] [7] [8] This protein family is known for regulating signal transduction pathways primarily through binding phosphoserine proteins, though it can also bind phosphothreonine proteins and unphosphorylated proteins.[2] [3] [4] [7] [10] By extension, 14-3-3 proteins are involved in a wide range of biological processes, including metabolism, transcription, apoptosis, protein transport, and cell cycle regulation.[4] [5] [7] [8] [11] This combination of dependence on phosphorylation and widespread biological impact results in dynamic regulation of multiple signalling pathways and allows for cellular adaptation to environmental changes.[4]

In particular, 14-3-3ζ is a key player in regulating cell survival and interacts with many apoptotic proteins, including Raf kinases, BAX, BAD, NOXA, and caspase-2.[4] [5] For the most part, 14-3-3ζ negatively regulates apoptosis by binding and sequestering BAD and BAX in the cytoplasm, effectively preventing activation of proapoptotic Bcl-2 and Bcl-XL, as well as by preventing NOXA from inhibiting antiapoptotic MCL1.[5] As a result, 14-3-3ζ functions to protect the cell from environmental stresses, such as chemotherapy-induced death, anoikis, growth factor deprivation, and hypoxia. As an example of its dynamic activity, 14-3-3ζ activates autophagy under hypoxic conditions by binding ATG9A, while it prevents autophagy under hyperglycemic conditions by binding Vps34.[4] Furthermore, 14-3-3ζ may regulate glucose receptor trafficking in response to insulin levels through its interaction with IRS1.[2] [4]

In addition to cell survival, 14-3-3ζ regulates cell cycle progression through various ligands and processes. For instance, 14-3-3ζ controls cellular senescence by complexing with BIS to chaperone protein folding of STAT3 and activate the signaling pathway.[12] Also, 14-3-3ζ can negatively regulate the G2-M phase checkpoint by binding and sequestering the cyclin-dependent kinases to the cytoplasm, thus inhibiting their activity.[13] Since 14-3-3ζ is predominantly found in the cytoplasm and binds many nuclear proteins, it likely prevents nuclear import by blocking the nuclear localization signal of target proteins.[8] Its localization to both the cytoplasm and nucleus also suggests a role in gene expression, possibly through regulation of transcription factor activity.[5]

Antigenic Function

Emerging literature shows the increased presence of the anti-14-3-3ζ antibodies in several immune dysfunctions, including human vasculitis and cancer.[14] [15] [16] The antigenic 14-3-3ζ can directly affect T cell differentiation into Th1 and Th17 cells, and thereby promotes IFN-gamma and IL-17 production.[17] The MHC class II presentation of 14-3-3ζ antigen strongly influence IFN-gamma production. The physiological significance of its antigenic role remains unknown

Signaling regulator

Intracellular 14-3-3ζ plays a role in interleukin-17 signaling. IL-17A is a proinflammatory cytokine involved in autoimmune diseases and host defense. The presence of 14-3-3ζ creates a bias in IL-17A signaling outcomes, by promoting the production of IL-6 while suppressing CXCL1.[18]

Clinical Significance

The14-3-3 protein zeta/delta (14-3-3ζ) is a protein (in humans encoded by the YWHAZ gene on chromosome 8) with an important apoptotic constituents. During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.[19] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.

As a major hub protein, 14-3-3ζ is involved in various diseases and disorders. For one, 14-3-3ζ plays a central role in cell proliferation and, by extension, tumor progression.[3] [6] The protein has been implicated in many cancers, including lung cancer, breast cancer, lymphoma, and head and neck cancer, through pathways such as mTOR, Akt, and glucose receptor trafficking. Notably, it has been associated with chemoresistance and, thus, is a promising therapeutic target for cancer treatment.[4] [5] [6] So far, it stands to become a prognostic marker for breast cancer, lung cancer, head and neck cancer, and possibly gastric cancer in patients who might require more aggressive treatment.[3] However, no statistically significant relationship was determined in hepatocellular carcinoma.[13]

In addition to cancers, 14-3-3ζ has been implicated in pathogenic infections and neurodegenerative diseases, including Creutzfeldt–Jakob disease, Parkinson's disease, and Alzheimer's disease (AD).[7] 14-3-3ζ has been observed to participate in AD through its interaction with tau protein, and its expression is correlated with disease severity.[10]

The human surfactant protein A, an innate immunity molecule (encoded by two genes SFTPA1 and SFTPA2) appears to be binding with the 14-3-3 protein family. Furthermore, inhibition of 14-3-3 was correlated with lower levels of the surfactant protein indicating a relationship between surface and 14-3-3 proteins.[20] Surfactant is an important element in the maintenance of lung and respiratory functions. A lack of surfactant is closely related to respiratory distress syndrome. Preterm neonates who exhibit neonatal respiratory distress syndrome (NRDS) exhibit a deficiency of surfactant. All together, the 14-3-3 protein may have a significant role in respiratory function and NRDS.[21] [22]

Furthermore, recent studies have shown the 14-3-3ζ plays a significant clinical role in the suppression of the RA symptoms in experimental animals. The 14-3-3ζ KO animals had early onset and severe inflammatory arthritis compared to wild-type. A significantly greater bone loss and immune cell infiltration in the synovial joints was observed in the arthritic 14-3-3ζ KO animals. It plays an active role in promoting collagen synthesis and bone preservation, thereby significantly impacting bone remodeling. Rescue with antibodies failed to suppress the arthritis, however, a 14-3-3ζ immunization in pre-symptomatic rats, both KO and wild type, resulted in significant suppression of the arthritis. Mechanistically, it was observed that 14-3-3ζ downregulates IL-1β and upregulates the IL-1 receptor antagonist, which results in arthritis suppression.[23]

Interactions

YWHAZ has been shown to interact with:

See also

Further reading

Notes and References

  1. Tommerup N, Leffers H . Assignment of the human genes encoding 14,3-3 Eta (YWHAH) to 22q12, 14-3-3 zeta (YWHAZ) to 2p25.1-p25.2, and 14-3-3 beta (YWHAB) to 20q13.1 by in situ hybridization . Genomics . 33 . 1 . 149–50 . April 1996 . 8617504 . 10.1006/geno.1996.0176 .
  2. Web site: Entrez Gene: YWHAZ tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide.
  3. Nishimura Y, Komatsu S, Ichikawa D, Nagata H, Hirajima S, Takeshita H, Kawaguchi T, Arita T, Konishi H, Kashimoto K, Shiozaki A, Fujiwara H, Okamoto K, Tsuda H, Otsuji E . 6 . Overexpression of YWHAZ relates to tumor cell proliferation and malignant outcome of gastric carcinoma . British Journal of Cancer . 108 . 6 . 1324–31 . April 2013 . 23422756 . 3619260 . 10.1038/bjc.2013.65 .
  4. Weerasekara VK, Panek DJ, Broadbent DG, Mortenson JB, Mathis AD, Logan GN, Prince JT, Thomson DM, Thompson JW, Andersen JL . 6 . Metabolic-stress-induced rearrangement of the 14-3-3ζ interactome promotes autophagy via a ULK1- and AMPK-regulated 14-3-3ζ interaction with phosphorylated Atg9 . Molecular and Cellular Biology . 34 . 24 . 4379–88 . December 2014 . 25266655 . 4248729 . 10.1128/MCB.00740-14 .
  5. Liang R, Chen XQ, Bai QX, Wang Z, Zhang T, Yang L, Dong BX, Gao GX, Gu HT, Zhu HF . 6 . Increased 14-3-3ζ expression in the multidrug-resistant leukemia cell line HL-60/VCR as compared to the parental line mediates cell growth and apoptosis in part through modification of gene expression . Acta Haematologica . 132 . 2 . 177–86 . 2014 . 24603438 . 10.1159/000357377 . 13410244 .
  6. Matta A, Siu KW, Ralhan R . 14-3-3 zeta as novel molecular target for cancer therapy . Expert Opinion on Therapeutic Targets . 16 . 5 . 515–23 . May 2012 . 22512284 . 10.1517/14728222.2012.668185 . 38941816 .
  7. Joo Y, Schumacher B, Landrieu I, Bartel M, Smet-Nocca C, Jang A, Choi HS, Jeon NL, Chang KA, Kim HS, Ottmann C, Suh YH . 6 . Involvement of 14-3-3 in tubulin instability and impaired axon development is mediated by Tau . FASEB Journal . 29 . 10 . 4133–44 . October 2015 . 26103986 . 10.1096/fj.14-265009 . free . 32696302 .
  8. Jérôme M, Paudel HK . 14-3-3ζ regulates nuclear trafficking of protein phosphatase 1α (PP1α) in HEK-293 cells . Archives of Biochemistry and Biophysics . 558 . 28–35 . September 2014 . 24956593 . 10.1016/j.abb.2014.06.012 .
  9. Killoran RC, Fan J, Yang D, Shilton BH, Choy WY . Structural Analysis of the 14-3-3ζ/Chibby Interaction Involved in Wnt/β-Catenin Signaling . PLOS ONE . 10 . 4 . e0123934 . 2015 . 25909186 . 4409382 . 10.1371/journal.pone.0123934 . 2015PLoSO..1023934K . free .
  10. Qureshi HY, Li T, MacDonald R, Cho CM, Leclerc N, Paudel HK . Interaction of 14-3-3ζ with microtubule-associated protein tau within Alzheimer's disease neurofibrillary tangles . Biochemistry . 52 . 37 . 6445–55 . September 2013 . 23962087 . 10.1021/bi400442d .
  11. Fang D, Hawke D, Zheng Y, Xia Y, Meisenhelder J, Nika H, Mills GB, Kobayashi R, Hunter T, Lu Z . 6 . Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity . The Journal of Biological Chemistry . 282 . 15 . 11221–9 . April 2007 . 17287208 . 1850976 . 10.1074/jbc.M611871200 . free .
  12. Lee JJ, Lee JS, Cui MN, Yun HH, Kim HY, Lee SH, Lee JH . BIS targeting induces cellular senescence through the regulation of 14-3-3 zeta/STAT3/SKP2/p27 in glioblastoma cells . Cell Death & Disease . 5 . 11 . e1537 . November 2014 . 25412315 . 4260756 . 10.1038/cddis.2014.501 .
  13. Zhang Y, Li Y, Lin C, Ding J, Liao G, Tang B . Aberrant upregulation of 14-3-3σ and EZH2 expression serves as an inferior prognostic biomarker for hepatocellular carcinoma . PLOS ONE . 9 . 9 . e107251 . 2014 . 25226601 . 4165773 . 10.1371/journal.pone.0107251 . 2014PLoSO...9j7251Z . free .
  14. Chakravarti R, Gupta K, Swain M, Willard B, Scholtz J, Svensson LG, Roselli EE, Pettersson G, Johnston DR, Soltesz EG, Yamashita M, Stuehr D, Daly TM, Hoffman GS . 6 . 14-3-3 in Thoracic Aortic Aneurysms: Identification of a Novel Autoantigen in Large Vessel Vasculitis . Arthritis & Rheumatology . 67 . 7 . 1913–21 . July 2015 . 25917817 . 4624269 . 10.1002/art.39130 .
  15. Qin J, Wang S, Wang P, Wang X, Ye H, Song C, Dai L, Wang K, Jiang B, Zhang J . 6 . Autoantibody against 14-3-3 zeta: a serological marker in detection of gastric cancer . Journal of Cancer Research and Clinical Oncology . 145 . 5 . 1253–1262 . May 2019 . 30887154 . 10.1007/s00432-019-02884-5 . 81980933 .
  16. Liu M, Liu X, Ren P, Li J, Chai Y, Zheng SJ, Chen Y, Duan ZP, Li N, Zhang JY . 6 . A cancer-related protein 14-3-3ζ is a potential tumor-associated antigen in immunodiagnosis of hepatocellular carcinoma . Tumour Biology . 35 . 5 . 4247–56 . May 2014 . 24390614 . 4096569 . 10.1007/s13277-013-1555-8 .
  17. McGowan J, Peter C, Chattopadhyay S, Chakravarti R . 14-3-3ζ-A Novel Immunogen Promotes Inflammatory Cytokine Production . Frontiers in Immunology . 10 . 1553 . 2019 . 31396202 . 6667649 . 10.3389/fimmu.2019.01553 . free .
  18. McGowan J, Peter C, Kim J, Popli S, Veerman B, Saul-McBeth J, Conti H, Pruett-Miller SM, Chattopadhyay S, Chakravarti R . 6 . 14-3-3ζ-TRAF5 axis governs interleukin-17A signaling . Proceedings of the National Academy of Sciences of the United States of America . 117 . 40 . 25008–25017 . October 2020 . 32968020 . 10.1073/pnas.2008214117 . 221884385 . 7547158 . 2020PNAS..11725008M . free .
  19. Kerr JF, Wyllie AH, Currie AR . Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics . British Journal of Cancer . 26 . 4 . 239–57 . August 1972 . 4561027 . 2008650 . 10.1038/bjc.1972.33 .
  20. Noutsios GT, Ghattas P, Bennett S, Floros J . 14-3-3 isoforms bind directly exon B of the 5'-UTR of human surfactant protein A2 mRNA . American Journal of Physiology. Lung Cellular and Molecular Physiology . 309 . 2 . L147-57 . July 2015 . 26001776 . 4504974 . 10.1152/ajplung.00088.2015 .
  21. Lewis J, Veldhuizen RA . Surfactant: current and potential therapeutic application in infants and adults . Journal of Aerosol Medicine . 9 . 1 . 143–54 . 1996 . 10160204 . 10.1089/jam.1996.9.143 .
  22. Filoche M, Tai CF, Grotberg JB . Three-dimensional model of surfactant replacement therapy . Proceedings of the National Academy of Sciences of the United States of America . 112 . 30 . 9287–92 . July 2015 . 26170310 . 4522812 . 10.1073/pnas.1504025112 . 2015PNAS..112.9287F . free .
  23. Kim. Joshua. Chun. Krista. McGowan. Jenna. Zhang. Youjie. Czernik. Piotr J.. Mell. Blair. Joe. Bina. Chattopadhyay. Saurabh. Holoshitz. Joseph. Chakravarti. Ritu. 2021-08-24. 14-3-3ζ: A suppressor of inflammatory arthritis. Proceedings of the National Academy of Sciences of the United States of America. 118. 34. e2025257118. 10.1073/pnas.2025257118. 1091-6490. 8403930. 34408018. 2021PNAS..11825257K . free .
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  26. Yang H, Masters SC, Wang H, Fu H . The proapoptotic protein Bad binds the amphipathic groove of 14-3-3zeta . Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology . 1547 . 2 . 313–9 . June 2001 . 11410287 . 10.1016/s0167-4838(01)00202-3 .
  27. Clark GJ, Drugan JK, Rossman KL, Carpenter JW, Rogers-Graham K, Fu H, Der CJ, Campbell SL . 6 . 14-3-3 zeta negatively regulates raf-1 activity by interactions with the Raf-1 cysteine-rich domain . The Journal of Biological Chemistry . 272 . 34 . 20990–3 . August 1997 . 9261098 . 10.1074/jbc.272.34.20990 . free .
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  35. Feng S, Christodoulides N, Reséndiz JC, Berndt MC, Kroll MH . Cytoplasmic domains of GpIbalpha and GpIbbeta regulate 14-3-3zeta binding to GpIb/IX/V . Blood . 95 . 2 . 551–7 . January 2000 . 10627461 . 10.1182/blood.V95.2.551 . 77799615 .
  36. Du X, Harris SJ, Tetaz TJ, Ginsberg MH, Berndt MC . Association of a phospholipase A2 (14-3-3 protein) with the platelet glycoprotein Ib-IX complex . The Journal of Biological Chemistry . 269 . 28 . 18287–90 . July 1994 . 10.1016/S0021-9258(17)32301-3 . 8034572 . free .
  37. Prymakowska-Bosak M, Hock R, Catez F, Lim JH, Birger Y, Shirakawa H, Lee K, Bustin M . 6 . Mitotic phosphorylation of chromosomal protein HMGN1 inhibits nuclear import and promotes interaction with 14.3.3 proteins . Molecular and Cellular Biology . 22 . 19 . 6809–19 . October 2002 . 12215538 . 134047 . 10.1128/mcb.22.19.6809-6819.2002 .
  38. Sliva D, Gu M, Zhu YX, Chen J, Tsai S, Du X, Yang YC . 14-3-3zeta interacts with the alpha-chain of human interleukin 9 receptor . The Biochemical Journal . 345 Pt 3 . 3 . 741–7 . February 2000 . 10642536 . 1220812 . 10.1042/0264-6021:3450741 .
  39. Birkenfeld J, Betz H, Roth D . Identification of cofilin and LIM-domain-containing protein kinase 1 as novel interaction partners of 14-3-3 zeta . The Biochemical Journal . 369 . Pt 1 . 45–54 . January 2003 . 12323073 . 1223062 . 10.1042/BJ20021152 .
  40. Waterman MJ, Stavridi ES, Waterman JL, Halazonetis TD . ATM-dependent activation of p53 involves dephosphorylation and association with 14-3-3 proteins . Nature Genetics . 19 . 2 . 175–8 . June 1998 . 9620776 . 10.1038/542 . 26600934 .
  41. Gannon-Murakami L, Murakami K . Selective association of protein kinase C with 14-3-3 zeta in neuronally differentiated PC12 Cells. Stimulatory and inhibitory effect of 14-3-3 zeta in vivo . The Journal of Biological Chemistry . 277 . 26 . 23116–22 . June 2002 . 11950841 . 10.1074/jbc.M201478200 . free .
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  43. De Valck D, Heyninck K, Van Criekinge W, Vandenabeele P, Fiers W, Beyaert R . A20 inhibits NF-kappaB activation independently of binding to 14-3-3 proteins . Biochemical and Biophysical Research Communications . 238 . 2 . 590–4 . September 1997 . 9299557 . 10.1006/bbrc.1997.7343 .
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  45. Nellist M, Goedbloed MA, de Winter C, Verhaaf B, Jankie A, Reuser AJ, van den Ouweland AM, van der Sluijs P, Halley DJ . 6 . Identification and characterization of the interaction between tuberin and 14-3-3zeta . The Journal of Biological Chemistry . 277 . 42 . 39417–24 . October 2002 . 12176984 . 10.1074/jbc.M204802200 . free .
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