Rajiv Kumar¹,², Magali Cucchiarini³, Madan Thangavelu⁴, Moganavelli Singh⁵ and Punit Dhar⁶
¹University of Delhi, Delhi, India
²NIET, National Institute of Medical Science, India
³Center of Experimental Orthopaedics, Saarland University Medical Center and Saarland University, Homburg/Saar, Germany
⁴Single Cell & Single Molecule Genomics, Genome Mapping & Analysis Biotechnology, Cambridge, UK
⁵Nano-Gene and Drug Delivery Laboratory, Dept. of Biochemistry, School of Life Sciences, University of KwaZulu-Natal (Westville Campus), Durban, South Africa
⁶Department of Surgical Gastroenterology, AIIMS, Rishikesh, Uttarakhand, India

Part of the book: Advances in Health and Disease. Volume 63

Abstract

All eukaryotic cells have a system in place called the ubiquitin-dependent proteolysis system to control protein degradation; nevertheless, any flaws in this system can initiate numerous fatal diseases, including cancer, metabolic problems, neurological disorders and diseases. These health complications interlink with faults in ubiquitin-dependent proteolysis. Ubiquitin assists as a post-translational targeting signal for altering the structure, localization of other proteins, features and functioning styles of the cells and tissues. The ubiquitin ligase standardizes the specific nature of the ubiquitination features and cellular response. The ubiquitin ligase is a critical element of the enzymatic cascade that regulates the part of the multipubiquitin chain to the target or labile protein. Consequently, the attachment of the ubiquitin topology is crucial for regulating healthy growth, differentiation, and protection of cells from damage by xenobiotics, infections, mutations, and environmental stresses. Protein degradation is adopted by the cells as a route to enduringly deactivate proteins. The 26S proteasome is responsible for ATP-dependent protein failure in the cytoplasm and nuclei of eukaryotes. Most proteins are covalently associated with a multi-ubiquitin chain and engage the 26S proteasome. In the testes, the ubiquitin ligases E1, E2, E3, and UBC4 are dynamic. Here, prompt and large protein alterations are essential for a cell to respond to its environment, and a complex web of interrelated events, including control over synthesis, localization, and degradation. The regulator of the cell cycle, receptor processing, growth management, and stress response are all subject to intracellular proteolysis. This chapter focuses on (I) the significant contribution of ubiquitination in the cellular signaling pathways that contract with these external influences; (II) the mechanisms of ubiquitination-deubiquitination that offer the system its high level of selectivity, (III) the role of ubiquitin-dependent degradation in initiating diseases in humans and forthcoming clinical claims developed to employ the cell’s built-in proteolytic machinery to cure diseases; (IV) to examine imaginable clinical practices fashioned to exploit the body’s own proteolytic machinery to cure the diseases, and analyze the effectiveness of vaccinations, antibodies, and other possible therapies that aim to block SARS-CoV-2 entrance pathways. Lastly, the authors include the most important unanswered queries pertaining to this crucial route.

Keywords: ubiquitin-dependent proteolysis, protein degradation, mechanisms of ubiquitination-deubiquitination, enzyme cascade, interface between health and disease

References

Abbas, R., & Larisch, S. (2021). Killing by degradation: Regulation of apoptosis by the
ubiquitin-proteasome-system. In Cells (Vol. 10, Issue 12).
https://doi.org/10.3390/cells10123465
Akasaka, Y., Ono, I., Kamiya, T., Ishikawa, Y., Kinoshita, T., Ishiguro, S., Yokoo, T.,
Imaizumi, R., Inomata, N., Fujita, K., Akishima-Fukasawa, Y., Uzuki, M., Ito, K., &
Ishii, T. (2010). The mechanisms underlying fibroblast apoptosis regulated by growth
factors during wound healing. Journal of Pathology.
https://doi.org/10.1002/path.2710
Aksenov, A. A., Da Silva, R., Knight, R., Lopes, N. P., & Dorrestein, P. C. (2017). Global
chemical analysis of biology by mass spectrometry. In Nature Reviews Chemistry
(Vol. 1). https://doi.org/10.1038/s41570-017-0054
Amaro, A. C., Samora, C. P., Holtackers, R., Wang, E., Kingston, I. J., Alonso, M.,
Lampson, M., McAinsh, A. D., & Meraldi, P. (2010). Molecular control of
kinetochore-microtubule dynamics and chromosome oscillations. Nature Cell
Biology, 12(4). https://doi.org/10.1038/ncb2033
Amerik, A. Y., & Hochstrasser, M. (2004). Mechanism and function of deubiquitinating
enzymes. In Biochimica et Biophysica Acta – Molecular Cell Research (Vol. 1695,
Issues 1–3). https://doi.org/10.1016/j.bbamcr.2004.10.003
Bader, N., Jung, T., & Grune, T. (2007). The proteasome and its role in nuclear protein
maintenance. In Experimental Gerontology (Vol. 42, Issue 9).
https://doi.org/10.1016/j.exger.2007.03.010
Bai, Z., Cao, Y., Liu, W., & Li, J. (2021). The sars-cov-2 nucleocapsid protein and its role
in viral structure, biological functions, and a potential target for drug or vaccine
mitigation. In Viruses (Vol. 13, Issue 6). https://doi.org/10.3390/v13061115
Boender, P. J., Heijtink, R. A., & Hellings, J. A. (1989). Nucleosomal fragments in serum
may directly reflect cell-mediated cytotoxic activity in vivo. Clinical Immunology and
Immunopathology, 53(1). https://doi.org/10.1016/0090-1229(89)90104-9
Breckel, C. A., & Hochstrasser, M. (2021). Ubiquitin ligase redundancy and nuclear cytoplasmic
localization in yeast protein quality control. In Biomolecules (Vol. 11,Issue 12).
MDPI. https://doi.org/10.3390/biom11121821
Budhavarapu, V. N., Chavez, M., & Tyler, J. K. (2013). How is epigenetic information
maintained through DNA replication? In Epigenetics and Chromatin (Vol. 6, Issue 1).
https://doi.org/10.1186/1756-8935-6-32
Bustos, F., Segarra-Fas, A., Nardocci, G., Cassidy, A., Antico, O., Davidson, L.,
Brandenburg, L., Macartney, T. J., Toth, R., Hastie, C. J., Moran, J., Gourlay, R.,
Varghese, J., Soares, R. F., Montecino, M., & Findlay, G. M. (2020). Functional
Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent
Neurodevelopmental Signaling. Developmental Cell, 55(5).
https://doi.org/10.1016/j.devcel.2020.09.025
Cadena, C., Ahmad, S., Xavier, A., Willemsen, J., Park, S., Park, J. W., Oh, S. W., Fujita,
T., Hou, F., Binder, M., & Hur, S. (2019). Ubiquitin-Dependent and -Independent
Roles of E3 Ligase RIPLET in Innate Immunity. Cell, 177(5).
https://doi.org/10.1016/j.cell.2019.03.017
Calabrò, M., Mandelli, L., Crisafulli, C., Sidoti, A., Jun, T. Y., Lee, S. J., Han, C., Patkar,
A. A., Masand, P. S., Pae, C. U., & Serretti, A. (2016). Genes Involved in
Neurodevelopment, Neuroplasticity, and Bipolar Disorder: CACNA1C, CHRNA1,
and MAPK1. Neuropsychobiology, 74(3). https://doi.org/10.1159/000468543
Chan, W. K. B., Olson, K. M., Wotring, J. W., Sexton, J. Z., Carlson, H. A., & Traynor, J.
R. (2022). In silico analysis of SARS-CoV-2 proteins as targets for clinically available
drugs. Scientific Reports, 12(1). https://doi.org/10.1038/s41598-022-08320-y
Chen, S. H., & Russell, D. H. (2015). How Closely Related Are Conformations of Protein
Ions Sampled by IM-MS to Native Solution Structures? Journal of the American
Society for Mass Spectrometry, 26(9). https://doi.org/10.1007/s13361-015-1191-1
Chen, X., Htet, Z. M., López-Alfonzo, E., Martin, A., & Walters, K. J. (2021). Proteasome
interaction with ubiquitinated substrates: from mechanisms to therapies. In FEBS
Journal (Vol. 288, Issue 18). https://doi.org/10.1111/febs.15638
CUSABIO: Manufacturer of validated ELISA Kits, antibodies and recombinant proteins.
CUSABIO: Manufacturer of validated ELISA Kits, antibodies and recombinant
proteins. (n.d.). CUSABIO: Manufacturer of validated ELISA Kits, antibodies and
recombinant proteins. https://www.cusabio.com/pathway/Ubiquitin-mediated proteolysis.html.
Dang, F., Nie, L., & Wei, W. (2021). Ubiquitin signaling in cell cycle control and
tumorigenesis. In Cell Death and Differentiation (Vol. 28, Issue 2).
https://doi.org/10.1038/s41418-020-00648-0
Databa, K. P. (n.d.). KEGG PATHWAY Databa. https://www.kegg.jp/kegg bin/show_pathway?ko03050
Ding, D., Ao, X., Liu, Y., Wang, Y. Y., Fa, H. G., Wang, M. Y., He, Y. Q., & Wang, J. X.
(2019). Post-translational modification of Parkin and its research progress in cancer.
In Cancer Communications (Vol. 39, Issue 1).
https://doi.org/10.1186/s40880-019-0421-5
Dissmeyer, N., Rivas, S., & Graciet, E. (2018). Life and death of proteins after protease
cleavage: protein degradation by the N-end rule pathway. New Phytologist, 218(3).
https://doi.org/10.1111/nph.14619
Do Patrocinio, A. B., Rodrigues, V., & Guidi Magalhães, L. (2022). P53: Stability from the
Ubiquitin-Proteasome System and Specific 26S Proteasome Inhibitors. In ACS Omega
(Vol. 7, Issue 5). https://doi.org/10.1021/acsomega.1c04726
Dumont, Alison, S. L., & Maillet, Laurent, Juin, Philippe P, Barillé-Nion, S. (2020). NOXA
the BCL-2 Family Member behind the Scenes in Cancer Treatment. Journal of
Cellular Signaling, 1(4). https://doi.org/10.33696/signaling.1.021
Fierabracci, A. (2014). The putative role of proteolytic pathways in the pathogenesis of
Type 1 diabetes mellitus: The “autophagy” hypothesis. Medical Hypotheses, 82(5).
https://doi.org/10.1016/j.mehy.2014.02.010
Fontes, F. L., Pinheiro, D. M. L., Oliveira, A. H. S. de, Oliveira, R. K. de M., Lajus, T. B.
P., & Agnez-Lima, L. F. (2015). Role of DNA repair in host immune response and
inflammation. In Mutation Research – Reviews in Mutation Research (Vol. 763).
https://doi.org/10.1016/j.mrrev.2014.11.004
Franić, D., Zubčić, K., & Boban, M. (2021). Nuclear ubiquitin-proteasome pathways in
proteostasis maintenance. In Biomolecules (Vol. 11, Issue 1, pp. 1–16). MDPI AG.
https://doi.org/10.3390/biom11010054
Fredrik Trulsson, Vyacheslav Akimov, Mihaela Robu, Nila van Overbeek, David
Aureliano Pérez Berrocal, Rashmi G. Shah, Jürgen Cox, Girish M. Shah, Blagoy
Blagoev, and A. C. O. V. (2022). Deubiquitinating enzymes and the proteasome
regulate preferential sets of ubiquitin substrates. Nat Commun., 13(2736), 1–17.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9117253/pdf/41467_2022_Article_30376.pdf
Frezza, M., Schmitt, S., & Ping Dou, Q. (2011). Targeting the Ubiquitin-Proteasome
Pathway: An Emerging Concept in Cancer Therapy. Current Topics in Medicinal
Chemistry, 11(23). https://doi.org/10.2174/156802611798281311
Gadhave, K., Bolshette, N., Ahire, A., Pardeshi, R., Thakur, K., Trandafir, C., Istrate, A.,
Ahmed, S., Lahkar, M., Muresanu, D. F., & Balea, M. (2016). The ubiquitin
proteasomal system: a potential target for the management of Alzheimer’s disease. In
Journal of Cellular and Molecular Medicine (Vol. 20, Issue 7).
https://doi.org/10.1111/jcmm.12817
Gang Xu, Yezi Wu, Tongyang Xiao, Furong Qi, Lujie Fan, Shengyuan Zhang, Jian Zhou,
Yanhua He, Xiang Gao, Hongxiang Zeng, Y. L. & Z. Z. (2022). Multiomics approach
reveals the ubiquitination-specific processes hijacked by SARS-CoV-2. Signal
Transduction and Targeted Therapy, 7(312), 1–13.
https://www.nature.com/articles/s41392-022-01156-y
Gilberto, S., & Peter, M. (2017). Dynamic ubiquitin signaling in cell cycle regulation. In
Journal of Cell Biology (Vol. 216, Issue 8). https://doi.org/10.1083/jcb.201703170
Gilfillan, A. M., & Beaven, M. A. (2011). Regulation of mast cell responses in health and
disease. Critical Reviews in Immunology, 31(6), 475–530.
https://doi.org/10.1615/critrevimmunol.v31.i6.30
Gupta, I., Singh, K., Varshney, N. K., & Khan, S. (2018). Delineating crosstalk mechanisms
of the ubiquitin proteasome system that regulate apoptosis. In Frontiers in Cell and
Developmental Biology (Vol. 6, Issue FEB). https://doi.org/10.3389/fcell.2018.00011
Hanpude, P., Bhattacharya, S., Dey, A. K., & Maiti, T. K. (2015). Deubiquitinating
enzymes in cellular signaling and disease regulation. In IUBMB Life
(Vol. 67, Issue 7). https://doi.org/10.1002/iub.1402
Harrigan, J. A., Jacq, X., Martin, N. M., & Jackson, S. P. (2018). Deubiquitylating enzymes
and drug discovery: Emerging opportunities. In Nature Reviews Drug Discovery
(Vol. 17, Issue 1). https://doi.org/10.1038/nrd.2017.152
Hartl, F. U. (2016). Cellular Homeostasis and Aging. In Annual Review of Biochemistry
(Vol. 85). https://doi.org/10.1146/annurev-biochem-011116-110806
Herrmann, J. M., Carvalho, P., Hayer-Hartl, M., & Yoshihisa, T. (2018). Life of proteins:
from nascent chain to degradation. Nature Structural and Molecular Biology, 25(11).
https://doi.org/10.1038/s41594-018-0150-5
Huang, W., Jiang, T., Choi, W., Qi, S., Pang, Y., Hu, Q., Xu, Y., Gong, X., Jeffrey, P. D.,
Wang, J., & Shi, Y. (2013). Mechanistic insights into CED-4-mediated activation of
CED-3. Genes and Development, 27(18). https://doi.org/10.1101/gad.224428.113
Ilmjärv, S., Abdul, F., Acosta-Gutiérrez, S., Estarellas, C., Galdadas, I., Casimir, M.,
Alessandrini, M., Gervasio, F. L., & Krause, K. H. (2021). Concurrent mutations in
RNA-dependent RNA polymerase and spike protein emerged as the epidemiologically
most successful SARS-CoV-2 variant. Scientific Reports, 11(1).
https://doi.org/10.1038/s41598-021-91662-w
Jones, R. D., Enam, C., Ibarra, R., Borror, H. R., Mostoller, K. E., Fredrickson, E. K., Lin,
J. B., Chuang, E., March, Z., Shorter, J., Ravid, T., Kleiger, G., & Gardner, R. G.
(2020). The extent of Ssa1/Ssa2 Hsp70 chaperone involvement in nuclear protein
quality control degradation varies with the substrate. Molecular Biology of the Cell,
31(3), 221–233. https://doi.org/10.1091/mbc.E18-02-0121
Kaplan, G. S., Torcun, C. C., Grune, T., Ozer, N. K., & Karademir, B. (2017). Protea-some
inhibitors in cancer therapy: Treatment regimen and peripheral neuropathy
as a side effect. In Free Radical Biology and Medicine (Vol. 103).
https://doi.org/10.1016/j.freeradbiomed.2016.12.007
Kerr, J. F. R., Wyllie, A. H., & Currie, A. R. (1972). Apoptosis: A basic biological
phenomenon with wide-ranging implications in tissue kinetics. British Journal of
Cancer, 26(4). https://doi.org/10.1038/bjc.1972.33
Kuhl, L. M., & Vader, G. (2019). Kinetochores, cohesin, and DNA breaks: Controlling
meiotic recombination within pericentromeres. Yeast, 36(3).
https://doi.org/10.1002/yea.3366
Kumar D, T., Shaikh, N., Kumar S, U., Doss C, G. P., & Zayed, H. (2021). Structure-Based
Virtual Screening to Identify Novel Potential Compound as an Alternative to
Remdesivir to Overcome the RdRp Protein Mutations in SARS-CoV-2. Frontiers in
Molecular Biosciences, 8. https://doi.org/10.3389/fmolb.2021.645216
Kumar, R. (2021). Emerging Role of Neutrophils in Wound Healing and Tissue Repair:
The Routes of Healing. Biomedical Journal of Scientific & Technical Research, 36(4),
28687–28688.
Kumar, R., Chhikara, B. S., Gulia, K., & Chhillar, M. (2021). Cleaning the molecular
machinery of cellsviaproteostasis, proteolysis and endocytosis selectively, effectively,
and precisely: intracellular self-defense and cellular perturbations. In Molecular
Omics (Vol. 17, Issue 1, pp. 11–28). Royal Society of Chemistry.
https://doi.org/10.1039/d0mo00085j
Kumar, R., & Gulia, K. (2021). The convergence of nanotechnology‐stem cell,
nanotopography‐mechanobiology, and biotic‐abiotic interfaces: Nanoscale tools for
tackling the top killer, arteriosclerosis, strokes, and heart attacks. Nano Select, 2(4),
655–687. https://doi.org/10.1002/nano.202000192
Lal, M., & Caplan, M. (2011). Regulated intramembrane proteolysis: Signaling pathways
and biological functions. In Physiology (Vol. 26, Issue 1).
https://doi.org/10.1152/physiol.00028.2010
Landau, G., Kodali, V. K., Malhotra, J. D., & Kaufman, R. J. (2013). Detection of oxidative
damage in response to protein misfolding in the endoplasmic reticulum. In Methods
in Enzymology (Vol. 526). https://doi.org/10.1016/B978-0-12-405883-5.00014-4
Lecker, S. H., Jagoe, R. T., Gilbert, A., Gomes, M., Baracos, V., Bailey, J., Price, S. R.,
Mitch, W. E., & Goldberg, A. L. (2004). Multiple types of skeletal muscle atrophy
involve a common program of changes in gene expression. The FASEB Journal, 18(1).
https://doi.org/10.1096/fj.03-0610com
Lee, B. H., Lee, M. J., Park, S., Oh, D. C., Elsasser, S., Chen, P. C., Gartner, C., Dimova,
N., Hanna, J., Gygi, S. P., Wilson, S. M., King, R. W., & Finley, D. (2010).
Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature,
467(7312). https://doi.org/10.1038/nature09299
Lippai, M., & Low, P. (2014). The role of the selective adaptor p62 and ubiquitin-like
proteins in autophagy. BioMed Research International, 2014.
https://doi.org/10.1155/2014/832704
Liu, Q., Yan, T., Tan, X., Wei, Z., Li, Y., Sun, Z., Zhang, H., & Chen, J. (2022).
Genome Wide Identification and Gene Expression Analysis of the OTU DUB Family in Oryza
sativa. Viruses, 14(2). https://doi.org/10.3390/v14020392
Livneh, I., Cohen-Kaplan, V., Cohen-Rosenzweig, C., Avni, N., & Ciechanover, A. (2016).
The life cycle of the 26S proteasome: From birth, through regulation and function, and
onto its death. In Cell Research (Vol. 26, Issue 8). https://doi.org/10.1038/cr.2016.86
Lub, S., Maes, K., Menu, E., De Bruyne, E., Vanderkerken, K., & Van Valckenborgh, E.
(2016). Novel strategies to target the ubiquitin proteasome system in multiple
myeloma. Oncotarget, 7(6). https://doi.org/10.18632/oncotarget.6658
Manecka, D. L., Vanderperre, B., Fon, E. A., & Durcan, T. M. (2017). The neuroprotective
role of protein quality control in halting the development of alpha-synuclein
pathology. In Frontiers in Molecular Neuroscience (Vol. 10). Frontiers Media S.A.
https://doi.org/10.3389/fnmol.2017.00311
Massaly, N., Francès, B., & Moulédous, L. (2015). Roles of the ubiquitin proteasome
system in the effects of drugs of abuse. Frontiers in Molecular Neuroscience, 7(JAN).
https://doi.org/10.3389/fnmol.2014.00099
McBride, W. H., Iwamoto, K. S., Syljuasen, R., Pervan, M., & Pajonk, F. (2003). The role
of the ubiquitin/proteasome system in cellular responses to radiation. In Oncogene
(Vol. 22, Issue 37 REV. ISS. 3). https://doi.org/10.1038/sj.onc.1206676
Mittal, N., Subramanian, G., Bütikofer, P., & Madhubala, R. (2013). Unique
posttranslational modifications in eukaryotic translation factors and their roles in
protozoan parasite viability and pathogenesis. In Molecular and Biochemical
Parasitology (Vol. 187, Issue 1). https://doi.org/10.1016/j.molbiopara.2012.11.001
Nguyen, K. T., Kim, J. M., Park, S. E., & Hwang, C. S. (2019). N-terminal methionine
excision of proteins creates tertiary destabilizing N-degrons of the Arg/N-end rule
pathway. Journal of Biological Chemistry, 294(12).
https://doi.org/10.1074/jbc.RA118.006913
Nguyen, K. T., Mun, S. H., Lee, C. S., & Hwang, C. S. (2018). Control of protein
degradation by N-terminal acetylation and the N-end rule pathway. In Experimental
and Molecular Medicine (Vol. 50, Issue 7).
https://doi.org/10.1038/s12276-018-0097-y
Nielsen, S. V., Poulsen, E. G., Rebula, C. A., & Hartmann-Petersen, R. (2014).
Protein quality control in the nucleus. In Biomolecules (Vol. 4, Issue 3).
https://doi.org/10.3390/biom4030646
Ogando, N. S., Dalebout, T. J., Zevenhoven-Dobbe, J. C., Limpens, R. W. A. L., van der
Meer, Y., Caly, L., Druce, J., de Vries, J. J. C., Kikkert, M., Barcena, M., Sidorov, I.,
& Snijder, E. J. (2020). SARS-coronavirus-2 replication in Vero E6 cells: Replication
kinetics, rapid adaptation and cytopathology. Journal of General Virology, 101(9).
https://doi.org/10.1099/jgv.0.001453
Pegoraro, G., Voss, T. C., Martin, S. E., Tuzmen, P., Guha, R., & Misteli, T. (2012).
Identification of mammalian protein quality control factors by high-throughput
cellular imaging. PLoS ONE, 7(2). https://doi.org/10.1371/journal.pone.0031684
Peng, Y., Du, N., Lei, Y., Dorje, S., Qi, J., Luo, T., Gao, G. F., & Song, H. (2020).
Structures of the SARS ‐CoV‐2 nucleocapsid and their perspectives for drug design.
The EMBO Journal, 39(20). https://doi.org/10.15252/embj.2020105938
Qi, F., & Zhang, F. (2020). Cell Cycle Regulation in the Plant Response to Stress. In
Frontiers in Plant Science (Vol. 10). https://doi.org/10.3389/fpls.2019.01765
Raiv Kumar. (2021). Ischemia-Reperfusion Injury: A Mechanistic Concept. Atheroscle rosis: Open Access, 6(4), 1–2.
Raiv Kumar. (2022). Routes of Infections, Inflammation, Immunity, Immunity Response
and Inflammatory Injury: Elucidation of a Biological Fight. Journal of Immunology
and Inflammation Diseases Therapy, 5(1), 1–4. https://auctoresonline.org/article/routes-of-infections-inflammation-immunity-immunity-response-and inflammatory-injury-elucidation-of-a-biological-fight
Rajiv, K. (2021a). Biomedical applications of nanoscale tools and nano-bio interface: A
blueprint of physical, chemical, and biochemical cues of cell mechanotransduction
machinery. Biomedical Research and Clinical Reviews, 4(2), 64, 1-4.
Rajiv, K. (2021b). Cell Shrinkage, Cytoskeletal Pathologies, and Neurodegeneration:
Myelin Sheath Formation and Remodeling.
Archives of Medical and Clinical Research, 1(1), 1–5.
Rajiv, K. (2021c). DNA Looping Initiating Types of Machinery of Transcription,
Recombination, and Replication: An Experimental, and Theoretical Insight. Global
Journal of Medical Research: B Pharma, Drug Discovery, Toxicology & Medicine,
21(2), 1–4. https://medicalresearchjournal.org/index.php/GJMR/article/view/2449
Rajiv, K. (2021d). Elucidation of the origin of autoimmune diseases via computational
multiscale mechanobiology and extracellular matrix remodeling: theories and
phenomenon of immunodominance. Current Medical and Drug Research, 5(1), Art.
ID 215 (2021).
Rajiv, K. (2021e). Healing, and Repair of Inflammatory Induced Injuries: Routes of
Rejuvenation. Aditum Journal of Clinical and Biomedical Research, 2(5), 1–3.
Rajiv, K. (2021f). Host-environment interface, host defense, and mast cell: autoimmunity,
allergy, inflammation, and immune response. JSM Clinical Pharmaceutics, 5(1), 1018, 1–4.
Rajiv, K. (2021g). Mechanosensors, and Mechanosensing: Mechanosensation, a Perception
of the Force and Response. Global Journal of Medical Research: C Microbiology and
Pathology, 21(2), 1–3. https://medicalresearchjournal.org/index.php/GJMR/article/view/2459
Rajiv, K. (2021h). Metabolic and immune system interface: immunometabolism, micro
biota, and diseases. Annals of Clinical and Medical Microbiology, 5(1), 1–3.
Rajiv, K. (2021i). Physiology, Coagulation Cascade: Inherited Disorders, and the
Molecular Phenomenon of Alterations in Hemostasis.
Journal of Clinical Haematology, 2(2), 62–64.
Rajiv, K. (2021j). Traumatic Brain Injury: Mechanistic Insight on Pathophysiological
Mechanisms Underlying, Neurotransmitters, and Potential Therapeutic
Targets. Medical and Clinical Reviews, 7(8), 1–3. https://medical-clinical reviews.imedpub.com/traumatic-brain-injury-mechanisticinsight-on pathophysiological-mechanismsunderlying-neurotransmitters-andpotential therapeutic-ta.pdf
Rajiv, K. (2022). A Mechanistic Insight on Pathophysiological Mechanisms of
Inflammatory Diseases and Potential Therapeutic Targets. Journal of Scientific
Research and Biomedical Informatics, 3(1), 1–4.
Rajiv Kumar, Sandeep Mittan, J. S. (2015). Nanobiomaterials, nanobiomechanics and
tissue bioengineering for advanced regenerative therapeutics: present and future
perspectives. Journal of Materials NanoScience, 2(1), 15–26.
Rajiv Kumar and Kiran Gulia. (2021). Cell Mechanotransduction Machinery, and Cell
Signaling Defects: Small Tools and Nano-Bio Interface for Influential Regenerative
Remedies. Journal of Cell Signaling, 6(5), 223, 1–14.
Rajiv Kumar and Mitrabasu Chhillar. (2021). Nano-bio interface, bioadaptability of
different nanoparticles, nanokicking and extracellular matrix mimicking: a biological
and medicinal front to promote the concept of a cell, having a better defense system
inbuilt by nature. Aditum Journal of Clinical and Biomedical Research, 1(5), 1–7.
Ramakrishna, S., Suresh, B., & Baek, K. H. (2011). The role of deubiquitinating enzymes
in apoptosis. In Cellular and Molecular Life Sciences (Vol. 68, Issue 1).
https://doi.org/10.1007/s00018-010-0504-6
Sadanandom, A., Bailey, M., Ewan, R., Lee, J., & Nelis, S. (2012). The ubiquitin proteasome system:
Central modifier of plant signalling. In New Phytologist (Vol. 196, Issue 1).
https://doi.org/10.1111/j.1469-8137.2012.04266.x
Scheffner, M., Nuber, U., & Huibregtse, J. M. (1995). Protein ubiquitination involving an
E1–E2–E3 enzyme ubiquitin thioester cascade. Nature, 373(6509).
https://doi.org/10.1038/373081a0
Schneider, K. L., Nyström, T., & Widlund, P. O. (2018). Studying Spatial Protein Quality
Control, Proteopathies, and Aging Using Different Model Misfolding Proteins in S.
Cerevisiae. In Frontiers in Molecular Neuroscience (Vol. 11). Frontiers Media S.A.
https://doi.org/10.3389/fnmol.2018.00249
Sclafani, R. A., & Holzen, T. M. (2007). Cell cycle regulation of DNA replication.
In Annual Review of Genetics (Vol. 41).
https://doi.org/10.1146/annurev.genet.41.110306.130308
Sontag, E. M., Vonk, W. I. M., & Frydman, J. (2014). Sorting out the trash: The spatial
nature of eukaryotic protein quality control. In Current Opinion in Cell Biology (Vol.
26, Issue 1, pp. 139–146). https://doi.org/10.1016/j.ceb.2013.12.006
Staropoli, J. F., & Abeliovich, A. (2005). The ubiquitin-proteasome pathway is necessary
for maintenance of the postmitotic status of neurons. Journal of Molecular
Neuroscience, 27(2). https://doi.org/10.1385/JMN:27:2:175
Stewart, M. D., Ritterhoff, T., Klevit, R. E., & Brzovic, P. S. (2016). E2 enzymes: More
than just middle men. In Cell Research (Vol. 26, Issue 4).
https://doi.org/10.1038/cr.2016.35
Surjit, M., & Lal, S. K. (2008). The SARS-CoV nucleocapsid protein: A protein with
multifarious activities. In Infection, Genetics and Evolution (Vol. 8, Issue 4).
https://doi.org/10.1016/j.meegid.2007.07.004
Swaney, K. F., Huang, C. H., & Devreotes, P. N. (2010). Eukaryotic chemotaxis: A network
of signaling pathways controls motility, directional sensing, and polarity. In Annual
Review of Biophysics (Vol. 39, Issue 1).
https://doi.org/10.1146/annurev.biophys.093008.131228
Tasaki, T., Zakrzewska, A., Dudgeon, D. D., Jiang, Y., Lazo, J. S., & Kwon, Y. T. (2009).
The substrate recognition domains of the N-end rule pathway. Journal of Biological
Chemistry, 284(3). https://doi.org/10.1074/jbc.M803641200
Taylor, R. C., Adrain, C., & Martin, S. J. (2005). Proteases, proteasomes and apoptosis:
Breaking Ub is hard to do. Cell Death and Differentiation, 12(9).
https://doi.org/10.1038/sj.cdd.4401703
Torres-Perez, J. V., Irfan, J., Febrianto, M. R., Di Giovanni, S., & Nagy, I. (2021). Histone
post-translational modifications as potential therapeutic targets for pain management.
In Trends in Pharmacological Sciences (Vol. 42, Issue 11).
https://doi.org/10.1016/j.tips.2021.08.002
Tu, Y., Chen, C., Pan, J., Xu, J., Zhou, Z. G., & Wang, C. Y. (2012). The ubiquitin
proteasome pathway (UPP) in the regulation of cell cycle control and DNA damage
repair and its implication in tumorigenesis. In International Journal of Clinical and
Experimental Pathology (Vol. 5, Issue 8).
Varshavsky, A. (2011). The N-end rule pathway and regulation by proteolysis. In Protein
Science (Vol. 20, Issue 8). https://doi.org/10.1002/pro.666
Vere, G., Kealy, R., Kessler, B. M., & Pinto-Fernandez, A. (2020). Ubiquitomics: An
overview and future. In Biomolecules (Vol. 10, Issue 10).
https://doi.org/10.3390/biom10101453
Yang, Q., Zhao, J., Chen, D., & Wang, Y. (2021). E3 ubiquitin ligases: styles, structures
and functions. In Molecular Biomedicine (Vol. 2, Issue 1).
https://doi.org/10.1186/s43556-021-00043-2
Zhang, H., Zheng, H., Zhu, J., Dong, Q., Wang, J., Fan, H., Chen, Y., Zhang, X., Han, X.,
Li, Q., Lu, J., Tong, Y., & Chen, Z. (2021). Ubiquitin-Modified Proteome of SARS CoV-2-Infected
Host Cells Reveals Insights into Virus-Host Interaction and
Pathogenesis. Journal of Proteome Research, 20(5).
https://doi.org/10.1021/acs.jproteome.0c00758
Zhang, J., Huang, J., Gu, Y., Xue, M., Qian, F., Wang, B., Yang, W., Yu, H., Wang, Q.,
Guo, X., Ding, X., Wang, J., Jin, M., & Zhang, Y. (2021). Inflammation-induced
inhibition of chaperone-mediated autophagy maintains the immunosuppressive
function of murine mesenchymal stromal cells. Cellular and Molecular Immunology,
18(6). https://doi.org/10.1038/s41423-019-0345-7
Zhang, L., Afolabi, L. O., Wan, X., Li, Y., & Chen, L. (2020). Emerging Roles of Tripartite
Motif-Containing Family Proteins (TRIMs) in Eliminating Misfolded Proteins. In
Frontiers in Cell and Developmental Biology (Vol. 8). Frontiers Media S.A.
https://doi.org/10.3389/fcell.2020.00802
Zhao, J., Tenev, T., Martins, L. M., Downward, J., & Lemoine, N. R. (2000).
The ubiquitin proteasome pathway regulates survivin degradation in a cell cycle-dependent manner.
Journal of Cell Science, 113(23). https://doi.org/10.1242/jcs.113.23.4363.