Deregulated Signaling Pathways in Inflammation and Cancer

Editorial

19 July 2024

Editorial: Deregulated signaling pathways in inflammation and cancer

Parameswaran Ramakrishnan

916 views

0 citations

Editors

Mumtaz Anwar

University of Illinois Chicago

Vijay Avin Balaji Ragunathrao

University of Illinois Chicago

Mohammad Tauseef

Department of Pharmaceutical Sciences, College of Pharmacy, Chicago State University

Parameswaran Ramakrishnan

Case Western Reserve University

Impact

TRIF-dependent TLR3 and TLR4 signaling. TLR4 forms a complex with MD-2, a secreted glycoprotein that recognizes and binds LPS through the participation of LBP and CD14. Subsequently, TLR4 is internalized to the membrane of the endosome and relies on bridge adaptor TRAM to initiate TRIF-dependent signaling. TLR3 is localized on the membrane of the endosome and activated by dsRNA, which interacts with TRIF directly. TRIF-dependent TLR3 signaling includes ①-⑧. TRIF-dependent TLR4 signaling includes ①-⑩. ① IFN-β response mediated by the N-terminal of TRIF downstream of TLR3 and TLR4. Upon activation of the TRAF3, the N-terminal of TRIF interacts with TBK1 and IKKε. TBK1 phosphorylates TRIF and then facilitates IRF3 binding to TRIF. Consequently, TBK1 phosphorylates IRF3 and IRF7, facilitating the formation of phosphorylated dimers for both proteins. These dimers subsequently translocate into the nucleus to initiate activation of the IFN-β response. ② NF-κB signaling mediated by the N-terminal of TRIF downstream of TLR3 and TLR4. TRIF recruits TRAF6, which then binds to TAK1 and TAB2 to activate IKKs. Subsequently, activated IKKs phosphorylate IκBα, thereby abolishing its inhibitory function on NF-κB complex and facilitating its activation. ③ NF-κB signaling mediated by the C-terminal of TRIF downstream of TLR3 and TLR4. The C-terminal of TRIF interacts with RIPK1 via their RHIM domains, followed by polyubiquitination events of RIPK1 which then facilitates the combination of TAK1 and TAB2, subsequently promoting IKKs activation, IκBα phosphorylatin, and NF-κB activation. ④ NF-κB signaling mediated by the C-terminal of TRIF downstream of TLR4. The C-terminal of TRIF interacts with RIPK1 through their RHIM domains, facilitating direct binding of RIPK1 to ERK1/2. Subsequently, phosphorylation of ERK1/2 occurs, inducing AP-1 activation and ultimately resulting in the expression of inflammatory factors. ⑤ RIPK3 competitively inhibits TRIF-dependent TLR3/TLR4-RIPK1-NF-κB signaling via its RHIM domain. RIPK3 interacts with RIPK1 through their RHIM domains. This interaction leads to the phosphorylation of RIPK1, thereby inhibiting RIPK1-dependent NF-κB activation processes. ⑥ Apoptosis signaling mediated by the RHIM domain of TRIF downstream of TLR3 and TLR4. The RHIM domain of TRIF allows it to bind to RIPK1. Once bound, RIPK1 recruits FADD through its DD domain, resulting in the activation of caspase8 and subsequently inducing apoptosis. ⑦-⑧ Necroptosis signaling mediated by the RHIM domain of TRIF downstream of TLR3 and TLR4. ⑦ In the presence of z-VAD, TRIF interacts with RIPK3 via their RHIM domains, then facilitates the accumulation of ROS, leading to the initiation of necroptosis. ⑧ When RIPK1 is absent, TRIF promotes the interaction between RIPK3 and MLKL, resulting in the phosphorylation of MLKL, thereby triggering necroptosis. During these processes, the FADD-caspase8 complex inhibits the activation of RIPK3 to restrain necroptosis. ⑨ NLRP3 inflammasome activation and mtDNA synthesis mediated by MyD88 and TRIF downstream of TLR4. MyD88 and TRIF trigger the transcription of CMPK2 with the involvement of IRF1, promoting the synthesis of mtDNA and ox-mtDNA, ultimately resulting in the activation of NLRP3 inflammasome. ⑩ TRIF activates the expression of SAMHD1 which exhibits a negative feedback role in mtDNA synthesis and IL-1β production.

Review

17 April 2024

TRIF-dependent signaling and its role in liver diseases

Lilin Hu

, 4 more and

Ling Yang

4,040 views

1 citations

Review

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Hippo pathway in intestinal diseases: focusing on ferroptosis

Hongwei Deng

, 5 more and

Jun Zhou

4,231 views

3 citations

The complex mechanism of action of ERK5 activation (Figure created using BioRender).

Mini Review

04 August 2023

The significance of ERK5 catalytic-independent functions in disease pathways

Nhat-Tu Le

3,530 views

4 citations

Adoptive T cell strategies to prevent immune suppression by TGF-β in TME. Multiple strategies are in development to modify T cells to target components of the TGB-β signaling pathway. T cells can be engineered to work against the immunosuppressive role of TGF-β, activated to induce a more efficient T cell cytotoxicity and prevent exhaustion. CAR T cells have been engineered to block the inhibitory effects of TGF-β by co-expressing a BCMA construct that expresses a dominant negative (DN) TGF-βRII armor. The DN TGF-βII lacks a functional receptor kinase domain which prevents TGF-β suppression despite prolonged exposure. CAR T cells have also been modified to express a decoy or a cytokine receptor that functionally converts inhibitory signals within the TME into pro-inflammatory signals. In addition, CAR T cells have been engineered to secrete a bispecific antibody that co-targets both PD-1 and TGF-βRII to improve anti-tumor immunity. T cells that express a TCR that engages the TGF-βRII to activate caspase recruitment domain-containing protein 11 (CARD11) and nuclear factor κ-B (NF-κB). Moreover, the inhibitory effects of SMAD7 on TGF-βRI promotes T cell mediated cytotoxicity. BiTE-expressing T cells simultaneous binding to CD3 in the TCR complex and the TGF-β to promote lytic enzymes that mediate CTL activity.

Review

12 December 2022

Targeting TGF-β signaling in the multiple myeloma microenvironment: Steering CARs and T cells in the right direction

Priyanka S. Rana

, 2 more and

James J. Driscoll

5,753 views

16 citations

Targets of the major anti-HIF-1α agents tested in clinical trials. Anti-HIF-1α agents directly or indirectly inhibit HIF-1α via different mechanisms. Anti-HIF-1α oligonucleotide EZN-2968 leads to the degradation of HIF-1α mRNA. Camptothecins irinotecan and topotecan downregulate HIF-1α via HIF-1α-targeting miRNAs. Digoxin and 2-methoxyestradiol (2ME2) suppress the translation of HIF-1α. Rapamycin analogs, like everolimus and temsirolimus, downregulate HIF-1α by inhibiting mTOR. Hsp90 inhibitor geldanamycin and HDAC inhibitors destabilize HIF-1α. Anthracyclines and the peptide antibiotic echinomycin block the binding of HIF-1α to DNA and thus inhibit HIF-1α action. Proteosome inhibitor bortezomib blocks the degradation of ubiquitinated HIF-1α and leads to the accumulation of HIF-1α in an inactive form. Additionally, it suppresses the expression of HIF-1α via inhibition of PI3K/Akt/mTOR and MAPK pathways. Abbreviations: Akt, Protein kinase B; CBP, cyclic AMP response element-binding protein; GF, Growth factor; HDAC, Histone deacetylase; HIF-1α, Hypoxia-inducible factor 1α; HIF-1β, Hypoxia-inducible factor 1β; HRE, Hypoxia response elements; HSP90, Heat shock protein 90; MAPK, Mitogen-activated protein kinase; mRNA, Messenger RNA; mTOR, The mammalian target of rapamycin; p300, transcriptional coactivator p300; PHD, prolyl hydroxylase; PI3K, Phosphoinositide 3-kinase; Ras, Ras GTPase; Ub, ubiquitin tag. Created with BioRender.com.

Review

08 February 2023

The hypoxia-inducible factor-1α in stemness and resistance to chemotherapy in gastric cancer: Future directions for therapeutic targeting

Gulnihal Ozcan

4,527 views

11 citations

Review

19 August 2022

The SIRT1-HMGB1 axis: Therapeutic potential to ameliorate inflammatory responses and tumor occurrence

Lanyi Wei

, 2 more and

Jinghui Zhai

Inflammation is a common complication of many chronic diseases. It includes inflammation of the parenchyma and vascular systems. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, which can directly participate in the suppression of inflammation. It can also regulate the activity of other proteins. Among them, high mobility group box 1 (HMGB1) signaling can be inhibited by deacetylating four lysine residues (55, 88, 90, and 177) in quiescent endothelial cells. HMGB1 is a ubiquitous nuclear protein, once translocated outside the cell, which can interact with various target cell receptors including the receptor for advanced glycation end-products (RAGE), toll-like receptor (TLR) 2, and TLR4 and stimulates the release of pro-inflammatory cyto-/chemokines. And SIRT1 has been reported to inhibit the activity of HMGB1. Both are related to the occurrence and development of inflammation and associated diseases but show an antagonistic relationship in controlling inflammation. Therefore, in this review, we introduce how this signaling axis regulates the emergence of inflammation-related responses and tumor occurrence, providing a new experimental perspective for future inflammation research. In addition, it explores diverse upstream regulators and some natural/synthetic activators of SIRT1 as a possible treatment for inflammatory responses and tumor occurrence which may encourage the development of new anti-inflammatory drugs. Meanwhile, this review also introduces the potential molecular mechanism of the SIRT1-HMGB1 pathway to improve inflammation, suggesting that SIRT1 and HMGB1 proteins may be potential targets for treating inflammation.

5,267 views

24 citations