14-3-3 protein eta also referred to as 14-3-3η is a protein that in humans is encoded by the YWHAH gene. Function This gene product belongs to the 14-3-3 family of proteins that are normally intracellular in nature and help to mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 99% identical to the mouse, rat and bovine orthologs. This gene contains a 7 bp repeat sequence in its 5' UTR, and changes in the number of this repeat has been associated with early-onset schizophrenia. Protein-protein interactions YWHAH has been shown to interact with: C-Raf, CDC25B, EPB41L3, Glucocorticoid receptor, KIF5B, KLC3, Phosphoinositide-dependent kinase-1, RIMS1, RIMS2, TLX2, TNFAIP3, and ZFP36. Externalization 14-3-3n is normally intracellular. Two main mechanisms resulting in the release of 14-3-3η into the extracellular environment have been reported: exosomal mediated process; and necroptosis; 14-3-3 proteins are components of small extracellular vesicles that are secreted by most, if not all cells. Tumor necrosis factor alpha stimulation of macrophages, but not IL-6, promotes the secretion of 14-3-3η into the extracellular space through a TNF alpha-dependent necroptotic mechanism. Role in rheumatoid arthritis A 2021 systematic literature review published by authors from the NHS Foundation Trust in the United Kingdom conclude the following about the 14-3-3n biomarker: adequate evidence for helping to assess the veracity of the diagnosis and severity of early rheumatoid arthritis (RA); can be combined with existing markers for severity and to provide possible ways of stratifying patients into more effective treatment groups; and a welcome new addition for rheumatologist’s diagnostic, treatment and strategy in RA. Role of extracellular 14-3-3η Exogenous 14-3-3η stimulation has been reported to stimulate various cell types including macrophages, monocytes, and fibroblast-like synoviocytes activating key cell signalling cascades including: JAK-STAT signaling pathway PI3K/AKT/mTOR pathway MAPK/ERK pathway JNK/AP-1 pathway FOXO3-SNAI1 Stimulation of cells by extracellular 14-3-3η has been reported to increase key factors relevant to the pathophysiology of rheumatoid arthritis, including: Tumor necrosis factor alpha Interleukin 6 CCL2/MCP-1 Matrix metalloproteinase (MMPs) RANKL Exogenous stimulation of human fibroblast-like synoviocytes, in a dose dependent manner, resulted in the development of invadosomes. Silencing of 14-3-3n via shRNA resulted in decreased invadosome formation. Invadosomes are finger-like projections that bud from the cell membrane and are directly associated with increasing the migratory or invasive potential of cells. In RA, this might account for how the disease travels