14-3-3 proteins generally form ~30 kDa-longhomo- or heterodimers.[12][13] Each of themonomers are composed of 9antiparallelalpha helices. Four alpha-helices (αC, αE, αG, and αI) form anamphipathic groove that serves as theligand binding site, which can recognize three types ofconsensus binding motifs: RXX(pS/pT)XP, RXXX(pS/pT)XP, and (pS/pT)X1-2-COOH (where pS/pT representsphosphorylated serine/threonine). In addition to these primary interactions, the target protein can also bind outside the groove via secondary interactions.In particular, thecrystallized structure of 14-3-3ζ forms a cup-shaped dimer when complexed with CBY.[13]TheYWHAZ gene encodes twotranscript variants which differ in the5' UTR but produce the same protein.[6]
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.[6][7][11][12] 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.[6][7][8][11][14] By extension, 14-3-3 proteins are involved in a wide range of biological processes, includingmetabolism,transcription, apoptosis,protein transport, andcell cycle regulation.[8][9][11][12][15] 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.[8]
In particular, 14-3-3ζ is a key player in regulating cell survival and interacts with many apoptotic proteins, includingRaf kinases,BAX,BAD,NOXA, andcaspase-2.[8][9] 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 antiapoptoticMCL1.[9] As a result, 14-3-3ζ functions to protect the cell from environmental stresses, such as chemotherapy-induced death,anoikis,growth factor deprivation, andhypoxia. As an example of its dynamic activity, 14-3-3ζ activatesautophagy under hypoxic conditions by bindingATG9A, while it prevents autophagy under hyperglycemic conditions by bindingVps34.[8] Furthermore, 14-3-3ζ may regulateglucosereceptor trafficking in response toinsulin levels through its interaction withIRS1.[6][8]
In addition to cell survival, 14-3-3ζ regulates cell cycle progression through various ligands and processes. For instance, 14-3-3ζ controlscellular senescence bycomplexing with BIS tochaperoneprotein folding ofSTAT3 and activate the signaling pathway.[16] Also, 14-3-3ζ can negatively regulate the G2-M phase checkpoint by binding and sequestering thecyclin-dependent kinases to the cytoplasm, thus inhibiting their activity.[17] Since 14-3-3ζ is predominantly found in the cytoplasm and binds manynuclear proteins, it likely preventsnuclear import by blocking thenuclear localization signal of target proteins.[12] Its localization to both the cytoplasm and nucleus also suggests a role ingene expression, possibly through regulation oftranscription factor activity.[9]
Emerging literature shows the increased presence of the anti-14-3-3ζ antibodies in several immune dysfunctions, including humanvasculitis andcancer.[18][19][20] Theantigenic 14-3-3ζ can directly affectT cell differentiation into Th1 and Th17 cells, and thereby promotes IFN-gamma and IL-17 production.[21] The MHC class II presentation of 14-3-3ζ antigen strongly influenceIFN-gamma production.[21] The physiological significance of its antigenic role remains unknown
Intracellular 14-3-3ζ plays a role ininterleukin-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 ofIL-6 while suppressingCXCL1.[22]
The14-3-3 protein zeta/delta (14-3-3ζ) is aprotein (in humans encoded by theYWHAZgene on chromosome 8) with an important apoptotic constituents. During a normalembryologic processes, or during cell injury (such as ischemia-reperfusion injury duringheart attacks andstrokes) or during developments and processes incancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of theDNA andnucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed byphagocytes, thereby preventing aninflammatory response.[23] 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 oppositemitosis 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 ofnecrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in manyphysiological andpathological processes. It plays an important role duringembryonal 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 variousdiseases and disorders. For one, 14-3-3ζ plays a central role incell proliferation and, by extension, tumor progression.[7][10] The protein has been implicated in many cancers, includinglung cancer,breast cancer,lymphoma, andhead and neck cancer, through pathways such asmTOR,Akt, and glucose receptor trafficking. Notably, it has been associated withchemoresistance and, thus, is a promising therapeutic target for cancer treatment.[8][9][10] So far, it stands to become aprognostic marker for breast cancer, lung cancer, head and neck cancer, and possiblygastric cancer in patients who might require more aggressive treatment.[7] However, no statistically significant relationship was determined inhepatocellular carcinoma.[17]
The humansurfactant 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.[24] Surfactant is an important element in the maintenance of lung and respiratory functions. A lack of surfactant is closely related torespiratory distress syndrome.Pretermneonates 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.[25][26]
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.[27]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Tommerup N, Leffers H (April 1996). "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.doi:10.1006/geno.1996.0176.PMID8617504.
^abcdefghiLiang R, Chen XQ, Bai QX, Wang Z, Zhang T, Yang L, et al. (2014). "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.doi:10.1159/000357377.PMID24603438.S2CID13410244.
^abcdeJérôme M, Paudel HK (September 2014). "14-3-3ζ regulates nuclear trafficking of protein phosphatase 1α (PP1α) in HEK-293 cells".Archives of Biochemistry and Biophysics.558:28–35.doi:10.1016/j.abb.2014.06.012.PMID24956593.
^abQureshi HY, Li T, MacDonald R, Cho CM, Leclerc N, Paudel HK (September 2013). "Interaction of 14-3-3ζ with microtubule-associated protein tau within Alzheimer's disease neurofibrillary tangles".Biochemistry.52 (37):6445–55.doi:10.1021/bi400442d.PMID23962087.
^Lewis J, Veldhuizen RA (1996). "Surfactant: current and potential therapeutic application in infants and adults".Journal of Aerosol Medicine.9 (1):143–54.doi:10.1089/jam.1996.9.143.PMID10160204.
^Yang H, Masters SC, Wang H, Fu H (June 2001). "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.doi:10.1016/s0167-4838(01)00202-3.PMID11410287.
^Zemlickova E, Dubois T, Kerai P, Clokie S, Cronshaw AD, Wakefield RI, et al. (August 2003). "Centaurin-alpha(1) associates with and is phosphorylated by isoforms of protein kinase C".Biochemical and Biophysical Research Communications.307 (3):459–65.doi:10.1016/S0006-291X(03)01187-2.PMID12893243.
^De Valck D, Heyninck K, Van Criekinge W, Vandenabeele P, Fiers W, Beyaert R (September 1997). "A20 inhibits NF-kappaB activation independently of binding to 14-3-3 proteins".Biochemical and Biophysical Research Communications.238 (2):590–4.doi:10.1006/bbrc.1997.7343.PMID9299557.
