{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T13:03:09Z","timestamp":1788440589854,"version":"build-2803163510"},"reference-count":196,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T00:00:00Z","timestamp":1739836800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The I\u03baB kinase (IKK) complex plays a central role in many signaling pathways that activate NF-\u03baB, which turns on a battery of genes important for immune response, inflammation, and cancer development. Ubiquitination is one of the most prevalent post-translational modifications of proteins and is best known for targeting substrates for proteasomal degradation. The investigations of NF-\u03baB signaling pathway primed the unveiling of the non-degradative roles of protein ubiquitination. The NF-\u03baB-essential modulator (NEMO) is the IKK regulatory subunit that is essential for IKK activation by diverse intrinsic and extrinsic stimuli. The studies centered on NEMO as a polyubiquitin-binding protein have remarkably advanced understandings of how NEMO transmits signals to NF-\u03baB activation and have laid a foundation for determining the molecular events demonstrating non-degradative ubiquitination as a major driving element in IKK activation. Furthermore, these studies have largely solved the enigma that IKK can be activated by diverse pathways that employ distinct sets of intermediaries in transmitting signals. NEMO and NEMO-related proteins that include optineurin, ABIN1, ABIN2, ABIN3, and CEP55, as non-degradative ubiquitin chain receptors, play a key role in sensing and transmitting ubiquitin signals embodied in different topologies of polyubiquitin chains for a variety of cellular processes and body responses. Studies of these multifaceted proteins in ubiquitin sensing have promoted understanding about the functions of non-degradative ubiquitination in intracellular signaling, protein trafficking, proteostasis, immune response, DNA damage response, and cell cycle control. In this review, I will also discuss how dysfunction in the NEMO family of protein-mediated non-degradative ubiquitin signaling is associated with various diseases, including immune disorders, neurodegenerative diseases, and cancer, and how microbial virulence factors target NEMO to induce pathogenesis or manipulate host response. A profound understanding of the molecular bases for non-degradative ubiquitin signaling will be valuable for developing tailored approaches for therapeutic purposes.<\/jats:p>","DOI":"10.3390\/cells14040304","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T06:41:12Z","timestamp":1739860872000},"page":"304","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["NEMO Family of Proteins as Polyubiquitin Receptors: Illustrating Non-Degradative Polyubiquitination\u2019s Roles in Health and Disease"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2923-9563","authenticated-orcid":false,"given":"Chuan-Jin","family":"Wu","sequence":"first","affiliation":[{"name":"Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1101\/gad.1228704","article-title":"Signaling to NF-kappaB","volume":"18","author":"Hayden","year":"2004","journal-title":"Genes Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1101\/gad.909001","article-title":"NF-kappaB signaling pathways in mammalian and insect innate immunity","volume":"15","author":"Silverman","year":"2001","journal-title":"Genes Dev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1126\/science.278.5339.860","article-title":"IKK-1 and IKK-2: Cytokine-activated IkappaB kinases essential for NF-kappaB activation","volume":"278","author":"Mercurio","year":"1997","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/26261","article-title":"IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex","volume":"395","author":"Rothwarf","year":"1998","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.cell.2008.01.020","article-title":"Shared principles in NF-kappaB signaling","volume":"132","author":"Hayden","year":"2008","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/ncb1384","article-title":"Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected]","volume":"8","author":"Wu","year":"2006","journal-title":"Nat. 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