"The Ubiquitin Proteasome Pathway (UPP) negates a wide variety of cellular processes, substrates and defects that can result in the pathogenesis of several important human diseases in multiple systems of the Human body .
The negation involves degradation of proteins via the Ubiquitin Proteasome Pathway (UPP) by assimilateing 2. discrete and successive steps:
- tagging the substrate protein by the covalent attachment of multiple ubiquitin molecules (Conjugation);
- and secondly the subsequent degradation of the tagged protein by the 26S proteasome, composed of the catalytic 20S core and the 19S regulator degraders.
- This classical function of ubiquitin is associated with housekeeping functions, regulation of protein turnover and antigeni‑peptide generation.
The UPP is highly regulated and the principal mechanism for protein catabolism in the mammalian cytosol, aqueous component of the cytoplasm of a cell, and nucleus.
The central role of the UPP in biology has been recognized with the Nobel Prize for Chemistry which was awarded to Avram Hershko, Aaron Ciechanover and Irwin Rose in 2004. The UPP is central to the regulation of almost all cellular processes including:
- Antigen processing
- Apoptosis
- Biogenesis of organelles
- Cell cycle and division
- DNA transcription and repair
- Differentiation and development
- Immune response and inflammation
- Neural and muscular degeneration
- Morphogenesis of neural networks
- Modulation of cell surface receptors, ion channels and the secretory pathway
- Response to stress and extracellular modulators
- Ribosome biogenesis
- Viral infection
More recently, it has become evident that protein modification by ubiquitin also has unconventional (non-degradative) functions such as the regulation of DNA repair and endocytosis. These non-traditional functions are dictated by the number of ubiquitin units attached to proteins (mono versus poly-ubiquitination) and also by the type of ubiquitin chain linkage that is present.
[Ubiquitin Proteasome Pathway, boston Biochem, Cambridge, MA 0239]
Humans have "Toll-like receptors. (TLRs) are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses.
The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, though the last three are not found in humans.[1] TLR's received their name from their similarity to the protein coded by the toll gene identified in Drosophila in 1985 by Christiane Nüsslein-Volhard and Eric Wieschaus.[2]
The ability of the immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of immune receptors called toll-like receptors (TLRs) that are expressed on the membranes of leukocytes including dendritic cells, macrophages, natural killer cells, cells of the adaptive immunity T cells, and B cells, and non immune cells (epithelial and endothelial cells, and fibroblasts).[3]
The binding of ligands - either in the form of adjuvant used in vaccinations or in the form of invasive moieties during times of natural infection - to the TLR marks the key molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity.[4][5]
Upon activation, TLRs recruit adapter proteins (proteins that mediate other protein-protein interactions) within the cytosol of the immune cell in order to propagate the antigen-induced signal transduction pathway. These recruited proteins are then responsible for the subsequent activation of other downstream proteins, including protein kinases (IKKi, IRAK1, IRAK4, and TBK1) that further amplify the signal and ultimately lead to the upregulation or suppression of genes that orchestrate inflammatory responses and other transcriptional events. Some of these events lead to cytokine production, proliferation, and survival, while others lead to greater adaptive immunity.[5]
If the ligand is a bacterial factor, the pathogen might be phagocytosed and digested, and its antigens presented to CD4+ T cells. In the case of a viral factor, the infected cell may shut off its protein synthesis and may undergo programmed cell death (apoptosis). Immune cells that have detected a virus may also release anti-viral factors such as interferons.
Toll-like receptors have also been shown to be an important link between innate and adaptive immunity through their presence in dendritic cells.[6] Flagellin, a TLR5 ligand, induces cytokine secretion on interacting with TLR5 on human T cells.[6]
TLRs are a type of pattern recognition receptor (PRR) and recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). TLRs together with the Interleukin-1 receptors form a receptor superfamily, known as the "interleukin-1 receptor / toll-like receptor superfamily"; all members of this family have in common a so-called TIR (toll-IL-1 receptor) domain.
Three subgroups of TIR domains exist. Proteins with subgroup 1 TIR domains are receptors for interleukins that are produced by macrophages, monocytes, and dendritic cells and all have extracellular Immunoglobulin (Ig) domains. Proteins with subgroup 2 TIR domains are classical TLRs, and bind directly or indirectly to molecules of microbial origin. A third subgroup of proteins containing TIR domains consists of adaptor proteins that are exclusively cytosolic and mediate signaling from proteins of subgroups 1 and 2.
- Mahla RS, Reddy MC, Prasad DV, Kumar H (September 2013). "Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology". Frontiers in Immunology. 4: 248. doi:10.3389/fimmu.2013.00248. PMC 3759294. PMID 24032031.
- Hansson GK, Edfeldt K (June 2005). "Toll to be paid at the gateway to the vessel wall". Arteriosclerosis, Thrombosis, and Vascular Biology. 25 (6): 1085–7. doi:10.1161/01.ATV.0000168894.43759.47. PMID 15923538.
- Delneste Y, Beauvillain C, Jeannin P (January 2007). "[Innate immunity: structure and function of TLRs]". Médecine/Sciences. 23 (1): 67–73. doi:10.1051/medsci/200723167. PMID 17212934.
- Takeda K, Akira S (January 2005). "Toll-like receptors in innate immunity". International Immunology. 17 (1): 1–14. doi:10.1093/intimm/dxh186. PMID 15585605.
- Medzhitov R, Preston-Hurlburt P, Janeway CA (July 1997). "A human homologue of the Drosophila Toll protein signals activation of adaptive immunity". Nature. 388 (6640): 394–7. Bibcode:1997Natur.388..394M. doi:10.1038/41131. PMID 9237759.
- Sharma N, Akhade AS, Qadri A (April 2013). "Sphingosine-1-phosphate suppresses TLR-induced CXCL8 secretion from human T cells". Journal of Leukocyte Biology. 93 (4): 521–8. doi:10.1189/jlb.0712328. PMID 23345392.
- Rolls A, Shechter R, London A, Ziv Y, Ronen A, Levy R, Schwartz M (September 2007). "Toll-like receptors modulate adult hippocampal neurogenesis". Nature Cell Biology. 9 (9): 1081–8. doi:10.1038/ncb1629. PMID 17704767.
