Ask about this productRelated genes to: Kimmy-1 Tollip
- Gene:
- TOLLIP NIH gene
- Name:
- toll interacting protein
- Previous symbol:
- -
- Synonyms:
- IL-1RAcPIP
- Chromosome:
- 11p15.5
- Locus Type:
- gene with protein product
- Date approved:
- 2003-03-13
- Date modifiied:
- 2016-10-05
Related products to: Kimmy-1 Tollip
Related articles to: Kimmy-1 Tollip
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) employs sophisticated strategies to subvert host innate immunity, a critical determinant of viral establishment and dissemination. Nevertheless, the immunomodulatory functions of coronavirus structural proteins remain incompletely understood. Here, we identify the evolutionarily conserved membrane (M) protein of SARS-CoV-2 as an innate immune antagonist that suppresses nuclear factor kappa-B (NF-κB) activation. Functional assays revealed that the M protein markedly inhibited NF-κB activation and reduced proinflammatory cytokine production in vitro. In lung epithelial M-expressing mouse, M significantly attenuated LPS-induced inflammation. Mechanistically, M protein from diverse coronaviruses directly interacts with host Toll-interacting protein (TOLLIP), stabilizing TOLLIP‒IRAK1 complex, preventing IRAK1 activation, thereby suppressing downstream NF-κB signaling and creating a permissive cellular microenvironment for viral replication. We mapped a conserved linker region within the M protein as the core motif mediating this interaction. This binding is highly conserved across coronaviruses, highlighting the fundamental role of the M-TOLLIP axis in viral immune evasion. Our findings reveal a conserved pan-coronavirus immune evasion strategy by which coronaviruses target TOLLIP to subvert Toll-like receptor (TLR)-NF-κB signaling. The conserved M-linker region thus represents a potential broad-spectrum antiviral target, providing a structural framework for developing next-generation antivirals against current and emerging coronavirus threats. - Source: PubMed
Publication date: 2026/06/17
Zhang YabinKang LuZhong YuShao SongjunXue SenrenLiu ChangliangZheng XiaoqiLin Jing-WenChen YuLuo FengmingWan Huajing - Autophagy plays a critical role in viral replication and the regulation of host immune responses. Although the TOM1-TOLLIP complex has been implicated in immune signaling, cargo trafficking, and endocytosis, its role in viral replication has not been defined. Here, we demonstrate that the SARS-CoV-2 main protease (NSP5) cleaves TOM1 at residue Q354 through its protease activity. This cleavage is also observed with the main proteases of SARS-CoV and MERS-CoV. Importantly, TOM1 overexpression suppresses SARS-CoV-2 replication in HEK293T-hACE2 and Vero cells, while TOM1 knockout via CRISPR-Cas9 significantly enhances viral propagation, indicating that TOM1 functions as a novel restriction factor against SARS-CoV-2 infection. Moreover, various TOM1 orthologs from diverse species, including cattle, bats, monkeys, mice, and ducks, show similar restriction to SARS-CoV-2, but they all are antagonized by NSP5 cleavage. Mechanistically, we found that TOM1 recruits the autophagy receptor TOLLIP to target SARS-CoV-2 envelope (E) protein for autophagic degradation, thereby limiting viral replication. These findings highlight the importance of the TOM1-TOLLIP complex in host defense and discover that SARS-CoV-2 exploits a conserved NSP5-mediated TOM1 cleavage mechanism to evade host antiviral defenses.IMPORTANCEViruses must overcome the body's natural defenses in order to replicate and spread. One important cellular defense mechanism is autophagy, a process that helps cells remove harmful proteins and pathogens. In this study, we discovered that a host protein called TOM1 acts as a restriction factor that helps limit the replication of SARS-CoV-2, the virus responsible for COVID-19. TOM1 works together with another protein, TOLLIP, to direct envelope proteins to the cell's degradation system, thereby reducing viral replication. However, SARS-CoV-2 has evolved a strategy to counter this defense. The viral main protease (NSP5) cleaves TOM1, disabling its antiviral activity. This mechanism is conserved among several coronaviruses, including SARS-CoV and MERS-CoV. Our findings reveal a previously unrecognized antiviral role of the TOM1-TOLLIP complex and demonstrate how coronaviruses evade this host defense, providing new insight into virus-host interactions and potential targets for antiviral therapies. - Source: PubMed
Publication date: 2026/06/12
Zhang QingxiangXin JingguoWang ChunleiZhang XueGao YuanGao WenyingZhang Wenyan - Single nucleotide polymorphisms (SNPs) within Toll interacting protein () coding gene have been associated with progression, prognosis and treatment response in idiopathic pulmonary fibrosis (IPF). These SNPs seem to influence mRNA expression and serum levels of TOLLIP. The aim of this study was to investigate serum concentrations in a previously genotyped cohort of patients with systemic sclerosis (SSc) with and without interstitial lung disease (ILD). - Source: PubMed
Publication date: 2026/06/09
Schröder NielsAndrä JitkaKnuth-Rehr DianaLeja SilkeHunzelmann NicolasBörner EdaBarbet KimberlyBonella Francesco - Intracellular signaling pathways are modulated by ubiquitin-dependent trafficking, in which specific plasma membrane receptors and cytosolic proteins are tagged, internalized, and degraded in the endolysosomal pathway. Target of Myb1 (TOM1) family proteins, including TOM1, TOM1-L1, and TOM1-L2 function as early adaptors within the ESCRT-0 machinery to recognize ubiquitinated cargo and coordinate its sorting. TOM1 proteins interact with ubiquitin and accessory proteins, such as TOLLIP, facilitating efficient cargo sequestration and endosomal maturation. These interactions are known to be modulated by pathogen-driven processes, such as Shigella flexneri-mediated phosphatidylinositol 5-phosphate accumulation, which can impair TOM1-dependent cargo trafficking. Beyond endosomal sorting, TOM1 contributes to autophagic flux by linking autophagosomes and endosomes through its interaction with the motor protein Myosin VI. Dysregulation of these pathways has been implicated in immune disorders, myocardial ischemia-reperfusion injury, and potentially tumorigenesis. In plants, TOM1-like proteins serve as functional ESCRT-0 analogs, mediating ubiquitin-dependent cargo sorting and integrating stress-responsive signaling. Recent studies have shed light on the modular organization of TOM1, revealing mechanisms of ubiquitin recognition, DXXLL motif function, and complex formation with adaptor proteins. Nonetheless, key questions remain regarding how TOM1 discriminates among ubiquitin linkages, interacts with distinct phosphoinositides under varying physiological conditions, and cooperates with TOLLIP during selective autophagy. Elucidating these mechanisms will advance our understanding of cellular transport and signaling and may reveal novel intervention targets for inflammatory and autoimmune diseases in humans as well as for improving drought tolerance and immune regulation in plants. - Source: PubMed
Publication date: 2026/05/26
Collins Megan VLång Heljä K MFinkielstein Carla VRyhänen Samppa JIkonen ElinaCapelluto Daniel G S - Cells can recover from sub-lethal necrosis by repairing plasma-membrane (PM) rupture through the ESCRT-III machinery, but how this process is regulated remains unknown. Here, we identify Toll-interacting protein (Tollip) as a conserved negative regulator for ESCRT-III-mediated PM repair. Quantitative proteomics revealed the enrichment of Tollip at damaged PM. Additionally, microscopy assays in mammalian cells and C. elegans confirmed the recruitment of Tollip to PM injury sites. Tollip deficiency augmented ESCRT-III assembly, improved long-term cell survival after sub-lethal PM damage, and enhanced PM repair, whereas Tollip overexpression suppressed these processes. Tollip translocation occurred independently of Ca⁺ influx, different from ESCRT-III. Functionally, by limiting PM repair and maintaining sub-lethal PM integrity loss, Tollip ensured optimal chemokine and cytokine production from the plasma-membrane-integrity (PMI) pathway, which is directly triggered by PM ruptures. Thus, Tollip acts as a molecular rheostat that links membrane damage repair and cell recovery to immune signaling. - Source: PubMed
Publication date: 2026/05/19
Ferrick Julia MMeng XinanMorgan EmilyKalvi AnthonyLi ZhenLi ChaoqunChang Chao-YuanXu SuhongGong Yi-Nan