Authors
Adnan Erol
Abstract
According to the current view, tumor necrosis factor (TNF) receptor 2 (TNFR2) provides neuroprotection and regeneration by activating both canonical and noncanonical NF-κB pathways when activated by paracrine membrane-bound TNF (mTNF). A careful analysis of the literature reveals, however, that mTNF-mediated TNFR2 stimulation only stimulates canonical NF-B signaling, which in turn inhibits the NF-κB-inducing kinase (NIK)-mediated noncanonical pathway. Moreover, microvesicles, which contain transmembrane TNF, secreted by activated microglia in response to danger signals also interact with TNFR2. Therefore, only cytoplasmic TNFR2 can initiate NIK activation following ligand-TNFR2 complex endocytosis. Activated NIK phosphorylates Drp1, promoting mitochondrial fission and inducing oxidative stress. Following that, oxidative stress and/or direct NIK activate c-Abl, a non-receptor tyrosine kinase that can initiate almost any neurodegenerative process. In conclusion, TNFR2 appears to be responsible for neurodegeneration as well while maintaining neuron viability, depending on the ligand.
Image 1
Main content
Introduction
When activated, TNFR2 signaling is considered to activate both canonical and non-canonical NF-κB signaling pathways, which support cellular viability. Therefore, therapeutic support for activating the TNFR2 pathway is being proposed as one of the leading options for controlling chronic inflammatory degenerative disorders [1]. However, this viewpoint may have some critical flaws that should be carefully examined in the context of neurodegenerative diseases. Although TNFR2 is primarily expressed in immune cells, its expression in both neuronal and glial cells has been validated [1–3]. TNFR2 binds to different ligands, resulting in diverse outcomes at the membrane level and the cytoplasm [1, 4]. While soluble TNF (sTNF) can bind with high affinity, it does not activate intact TNFR2 signaling. Therefore, the natural ligand of TNFR2 is membrane-bound TNF (mTNF) [5]. In resting cells, TRAF2 and TRAF3 interact with cIAPs, probably at the perinuclear endoplasmic reticulum (ER) area. This complex is associated with the E2 protein Ubc6, which is required for the degradative E3 ligase activity of cIAPs [2]; subsequently, it enables the cIAP-mediated ubiquitination and degradation of TRAF3-associated NIK [3]. In response to mTNF paracrine stimulation by glial cells, astrocytes, and, in particular, neuronal TNFR2 oligomerizes in the membrane. Thus, activated TNFR2 recruits the adapter molecule TRAF2 in a complex with TRAF3, cIAPs, and TRAF3-associated NIK [4]. TRAF2 also interacts with Parkin [5] and mitochondria [6]. Parkin, in turn, interacts with both NEMO and LUBAC, which is necessary for the linear ubiquitination of NEMO [7]. Furthermore, NF-κB and its upstream regulatory proteins, including IKKα and IKKβ, were also previously identified in mitochondria [8]. Activated TNFR2 interacts with mitochondria-associated TRAF2. This interaction facilitates the lysine 63 (K63)-linked ubiquitination of TRAF2 by cIAPs [9]. In addition, Parkin-recruited LUBAC, which is associated with OTULIN, decorates the outer membrane of mitochondria with methionine (M)1-linked ubiquitin chains. This promotes the assembly of an NF-κB signaling platform at the mitochondria. Surprisingly, HOIP, the catalytic component of LUBAC, interacts with PINK1 and stabilizes it through the modification of M1-linked ubiquitin chains. The activated PINK1 on mitochondria, in turn, phosphorylates linear ubiquitin chains, preventing their hydrolysis by the deubiquitinase OTULIN without dissipating the mitochondrial membrane potential [10]. Together, K63-linked and M1-linked ubiquitin chains create a docking platform for NEMO and TAK1 [9]. Thus, NEMO and TAK1 activate IKKα and IKKβ for the induction of the canonical NF-κB signaling pathway [1,9]. Subsequently, TNFR2-mediated NF-κB activation can protect neurons by modulating the p300/Stat3/RelA/OPA1 signaling cascade. This can significantly improve mitochondrial integrity and adaptive responses and support neurons’ ability to withstand stress [11]. NFKB activity also induces transcriptional up-regulation of anti-apoptotic genes, which support neural viability. Activated IKKα alone has previously been shown to directly phosphorylate NIK, causing NIK destabilization and thus inhibiting the hyperactivity of the noncanonical NF-kB pathway [12]. However, a later study reported that activating the heterotrimeric IKK complex (NEMO, IKKα, and IKKβ), but not IKKα alone, inhibits the activation of noncanonical NF-B signaling by phosphorylating and inhibits NIK activity [13]. In other words, the canonical NF-kB signaling pathway must be activated to control NIK activity and the associated noncanonical NF-kB pathway. TNF has been identified as a neuroprotective cytokine that prevents neuronal damage under various stress conditions. Furthermore, neuronal survival requires constitutive NF-κB activation via para- or autocrine loops [14,15]. A recent study has excellently shown that after TNF stimulation, intact mitochondria can provide a platform for the activation of NF-κB transcription factors and then transport them to the nucleus [10]. This mode of transport may be particularly important for polarized cells such as neurons. NF-κB regulates energy metabolism networks by balancing glycolysis utilization and mitochondrial respiration [16]. Under normal metabolic conditions, the "resting" brain consumes glucose and metabolizes it almost entirely to CO2 via mitochondrial oxidative phosphorylation [17]. Taken together, TNFR2 signaling induced by paracrine mTNF and the resulting NF-B activation protects neuronal viability and regulates synaptic plasticity [1] (Figure A). An unconventional third mode of TNF signaling is proposed in addition to conventional sTNF and mTNF signaling. In response to danger signals, the transmembrane TNF (tmTNF) is packaged into potent, pro-inflammatory microvesicles (MVs), which protect the enclosed TNF, allowing effective signaling to target cells [18]. Extracellular MVs carrying tmTNF are released by activated microglia interact preferentially with TNFR2 in neurons [18–20] and may form a ligand-receptor complex that undergoes endocytosis [20,21]. TRAF2, TRAF3, and E3 ubiquitin ligase cIAP1/2 are all associated with the cytoplasm, and TRAF3 functions as a NIK binding adapter. The unconventional ligation of TNFR2 translocates this complex to the perinuclear ER compartment where Ubc6 resides. Thus, cIAP and Ubc6 work together to degrade TRAF2 and TRAF3 by catalyzing K48-linked ubiquitination [2,22,23]. TNFR2-induced TRAF2/TRAF3 degradation may release NIK and the accumulated NIK promotes the activation of the noncanonical NF-κB signaling [23]. Altogether, only danger signals-induced unconventional TNF stimulation, but not mTNF may enable TNFR2-mediated NIK accumulation. Consequently, the widely accepted view that TNFR2 stimulation causes simultaneous canonical and non-canonical NF-κB activation may need to be reconsidered. Once NIK is stabilized, it phosphorylates IKKα and results in phosphorylation-dependent ubiquitination of NF-κB precursor protein p100, liberating the p52 subunit, which forms a heterodimer complex with RelB for the activation of noncanonical NF-κB pathway [24]. The cellular outputs of the noncanonical NF-κB pathway are ultimately determined by p52:RelB dimer-mediated gene processing. Hyperactivity of this pathway plays an important role in the etiopathogenesis of some proliferative and autoimmune diseases [25]. Remarkably, RelB expression levels were found to be very low in neurons [26]. Moreover, It has even been claimed that increased NIK expression in neurons, surprisingly, inhibits rather than activates NF-κB. Accordingly, the same study states that glia and other non-neuronal cell types are responsible for almost all of the NF-κB activity observed in the brain [27]. NIK may induce some essential biological functions beyond the activation of the noncanonical NF-κB pathway. NIK forms a complex with the mitochondria-associated fission protein Drp1 and phosphorylates it at serine 616 [28]. NIK also associates with the mitochondrial membrane protein PGAM5, which is required for the GTPase activity of Drp1 by dephosphorylating the serine 637 [29]. Consequently, NIK interaction with Drp1 at the outer membrane of mitochondria may induce mitochondrial fission, which can induce oxidative stress by increasing ROS production and oxygen consumption [28,30]. Mitochondrial abnormalities, in which NIK plays important causal roles, are strongly linked to the development of peripheral insulin resistance [31,32]. Analogous to its effects on peripheral glucose metabolism, it seems plausible to predict that NIK activation in the brain would directly contribute to insulin resistance and glucose intolerance which play a key role in neurodegeneration [33,34]. Interestingly, TNFR signaling can be activated independently of TNF in the presence of oxidative stress by self-dimerization of the receptor [35]. In line with this, NIK is linked to and required for the formation of the RIPK1/FADD/caspase-8 apoptotic death complex IIb [36]. Furthermore, a recent study demonstrated that NIK attenuates the cell protective function of JAK/STAT signaling, which has been shown to protect neurons [37] by phosphorylating JAK2 [38]. It has been previously reported that oxidative stress activates c-Abl, a non-receptor tyrosine kinase, in neurons [39] TNFR2-driven NIK activation and resultant oxidative stress may cause in the threonine 735 (T735) phosphorylation and cytoplasmic translocation of c-Abl [40]. NIK has also been shown to initiate the cytoplasmic activity of c-Abl by direct phosphorylating T735 [41]. Oxidative stress, protein aggregate deposition, and damaged mitochondria are hallmarks of neurodegenerative diseases [42]. Studies have shown that aberrant c-Abl activation causes neuroinflammation by promoting all these parameters [39,43]. The following are some of the major effects of activated and cytoplasmic localized c-Abl that may contribute to neurodegenerative pathologies. 1) Neurodegenerative diseases are characterized by the proliferation of activated microglia. Microglia are activated in response to PAMP, DAMP, and other environmental stimuli. Remarkably, increased TNF secretion was observed in activated microglia due to c-Abl and c-Abl-induced PKCδ activation [44]. c-Abl also activates p38 MAPK [45], which triggers plasma membrane pore formation and shedding of TNF-containing microvesicles from microglia, contributing to unconventional TNF signaling. 2) c-Abl phosphorylates OTULIN at tyrosine 56 (Y56); this abolishes the interaction between OTULIN and LUBAC [46], facilitating the interaction between LUBAC and SPATA2-bound CYLD [47]. SPATA2 is an allosteric activator of CYLD, a deubiquitinase for K63-linked ubiquitin chains. Thus, CYLD both inhibits TNFR-mediated NF-kB activation and induces cell death signaling [48]. Furthermore, Y56 phosphorylated OTULIN interacts with β-catenin, causing aberrant Wnt/β-catenin activation [46], which is involved in the development of most neurodegenerative diseases [49]. 3) c-Abl interacts with the PSMA7, a subunit of the 20S proteasome core complex, and phosphorylates at tyrosine 153, leading to the inhibition of proteasomal activity [50]. Proteasomal dysfunction, in turn, may result in protein accumulation and aggregation, as well as a loss of proteostasis, all of which contribute to neurodegenerative diseases [51]. 4) c-Abl phosphorylates hAha1 at tyrosine 223, promoting Hsp90 association and thus increasing Hsp90 ATPase activity. Thus, Hsp90 interaction with kinase clients improves, while chaperoning of non-kinase clients is compromised [52]. Because the majority of kinase clients are involved in oncogenesis, Hsp90 has been suggested as a facilitator of "oncogene addiction"[53]. In contrast, increased Hsp90 ATPase activity reduces its binding to proteins involved in neurodegenerative disorders, such as α-synuclein, promoting aggregate formation [54]. Overall, increased binding of hAha1 to Hsp90 may contribute to the accumulation of toxic proteins and neurotoxicity [55]. 5) c-Abl phosphorylates tau at tyrosine 394 [56,57]. Tyrosine-phosphorylated tau accumulates in intracellular aggregates, implying that tyrosine phosphorylation influences tau filament formation [58]. 6) c-Abl was shown as a major regulator of Parkin function by phosphorylating it on tyrosine 143. Parkin's ubiquitin ligase and cytoprotective activities are lost because of this post-translational modification, and its substrates, PARIS in particular, accumulate [59]. 7) Aside from contributing to PARIS accumulation, c-Abl phosphorylates PARIS at tyrosine 137, which is required for PARIS-induced cytotoxicity, including inhibition of the PGC-1-NRF1 pathway [60]. PARIS protein accumulation, on the other hand, can activate c-Abl tyrosine kinase, creating a pathological feed-forward loop [61]. 8) c-Abl phosphorylates α-synuclein at tyrosine 39, facilitating aggregation [62] and prion-like propagation of α-synuclein, which is important in neurodegeneration progression [63]. 9) c-Abl potentiates p53 activity by inhibiting Mdm2, an E3 ligase that is responsible for p53 degradation [64]. Thus, cytoplasmic accumulation of p53 may repress autophagy [65]. Surprisingly, α-synucleinopathy was found to activate both c-Abl and p53, inhibiting autophagy [66]. Taken together, another feed-forward regulation between c-Abl activation and α-synuclein accumulation could exacerbate the existing pathology. 10) c-Abl phosphorylates caveolin-1, a plasma membrane protein, at tyrosine 14 (Y14) [67], which regulates lipid raft-dependent macromolecular transcytosis in neurons. Therefore, c-Abl-mediated phosphorylation of caveolin-1 is important in cell-to-cell α-synuclein transmission and promotes the formation of Lewy bodies-like inclusion bodies [68]. Given that, TNFR2 has a higher TNF transcytosis capacity than TNFR1 [69]; it is conceivable that Y14 phosphorylated caveolin-1 may further enhance unconventional TNF signaling, thus causing another of the pathological feed-forward loops.
An axiomatic approach to the aforementioned neurodegeneration data.
The current prevailing view is that when stimulated, TNFR2 promotes neuronal viability by activating both canonical and noncanonical NF-κB pathways. Given the proinflammatory effects of increased NF-B activation in neurons, the question of what the teleological advantage of simultaneously stimulating both NF-κB pathways by TNFR2 may arise. Indeed, it has been demonstrated that TNFR2 in the CNS may respond differently to various conditions and ligands, resulting in diverse outcomes. In light of the above-described detailed data, the model to be presented is more likely to be rational. In the resting state, cross-talk with glial cells, astrocytes in particular, through TNFR2-mTNF and the resultant basal NF-kB activation are required for neuronal cell viability. Microglia, CNS innate immune cells, on the other hand, mediate the cytokine-induced inflammatory response primarily through the secretion of mobile vesicles in response to danger signals. MVs, containing TmTNF, secreted by microglia may interact with neural TNFR2. Endocytosis and the translocation of the tmTNF-TNFR2 complex to the perinuclear space can activate NIK. Given that neurodegenerative diseases are caused by the presence of predisposing gene alleles (risk genes) that interact with harmful environmental stimuli [70], it is clear that unregulated NIK activation will contribute to the pathology required for neurodegeneration. Thus, aberrantly activated NIK itself is detrimental to neuronal homeostasis. Furthermore, cytoplasmic activation of c-Abl by NIK or indirectly by NIK-Drp1-mediated mitochondrial fission triggers nearly all processes required for the pathogenesis of neurodegeneration. Furthermore, the resultant pathological feedforward loops create cytotoxicity through some important dysfunctions such as mitochondrial abnormalities, ubiquitinated protein accumulation due to simultaneous proteasome and autophagy inhibition, and increased pro-death activity (Figure B). Activation of NIK and c-Abl, two main interrelated kinases that can cause neurodegeneration following cytoplasmic activity of TNFR2, brings treatment options as well. The first of these is NIK inhibition. Currently, several small molecule inhibitors targeting NIK have been developed. However, given the importance of NIK activity in systemic immune regulation, NIK inhibition does not seem like a good choice due to potential systemic adverse effects. Endogenous c-Abl kinase activity is regulated by a wide range of stimuli, including growth factors, chemokines, DNA damage, oxidative stress, and adhesion receptors, as well as microbial pathogens. In response to various growth factors and antigenic stimuli, c-Abl regulates mitogenic activity in normal cells [71]. Emerging evidence suggests that proliferative and cell cycle activities promoted by activated c-Abl are known to contribute to the development of cancer and neurodegenerative diseases [72,73]. Therefore, tyrosine kinase inhibitors (TKIs) for c-Abl are employed to suppress hyperactive kinase activity in various pathologies [71,74]. The application of second and third-generation TKIs resulted in faster and more promising responses. However, their successful outcomes are frequently accompanied by a more severe toxicity profile and drug resistance [75]. Therefore, rather than inhibiting the total activity of c-Abl, the second option should be to control its cytoplasmic activity. In the cytoplasm, c-Abl undertakes the task of preparing postmitotic cells for programmed death in the face of threatening danger signals. T735 phosphorylation of c-Abl, which does not occur in a normally functioning cell, can be considered a marker of abnormal activity that impairs cellular homeostasis. In other words, it could be anticipated that inhibiting the presence of c-Abl in the cytoplasm would not be harmful to the healthy cells of the organism. Taken together, the development of a therapeutic strategy targeting T735 phosphorylation, which initiates the pathology-inducing cytoplasmic translocation of c-Abl, appears more encouraging. Finally, T735 phosphorylation of c-Abl in the cytoplasm can simply put, promote carcinogenesis in mitotically active cells and neurodegeneration in postmitotic neurons. Therefore, future T735 phosphorylation inhibitors of c-Abl would thus have the advantage of “killing two birds with one stone,” so to speak. CONFLICT OF INTEREST The author has no conflict of interest to report
Further details
Keywords
c-Abl; Drp1; NF-κB; NIK; neurodegeneration; oxidative stress; TNF; TNFR2
Abbreviations used
cIAP: cellular inhibitor of apoptosis; CNS: central nervous system; DAMP: damage‐associated molecular pattern; Drp1: dynamin-related protein 1; E2: ubiquitin-conjugating enzyme; FADD: Fas-associated protein with death domain; hAha1: human activator of Hsp90 ATPase 1; Hsp90: heat shock protein 90; IKK: inhibitor of nuclear factor kappa B kinase; IKK: Inhibitor of nuclear factor kappa-B kinase; JAK: Janus kinase; LUBAC: linear ubiquitin chain assembly complex; NEMO: NF-kappaB essential modulator; NF-κB: nuclear factor-kappa B; NIK: NF-kappaB-inducing kinase; NIK: NF-κB-inducing kinase; NRF1: nuclear Respiratory Factor 1; OTULIN: OTU DUB with linear specificity; PAMP: Pathogen‐associated molecular pattern; PARIS: parkin interacting substrate; PGAM5: Phosphoglycerate mutase 5; PGC1: peroxisome proliferator-activated receptor gamma coactivator 1; PINK1: PTEN-induced putative kinase 1; PKCδ: Protein kinase C-delta; PSMA7: Proteasome 20S Subunit Alpha 7; RIPK1: Receptor-interacting protein kinase 1; ROS: reactive oxygen species; SPATA2: Spermatogenesis Associated 2; STAT: Signal transducer and activator of transcription; TAK1: transforming growth factor-β-activated kinase 1; TNF: tumor necrosis factor; TNFR: Tumor necrosis factor receptor; TRAF: TNF receptor-associated factor; Ubc6: E2 ubiquitin-conjugating enzyme 6
Figure legend
Figure 1. Opposed neuronal functions of TNFR2 reminiscent of Dr. Jekyll and Mr. Hyde. (A) In the resting state, TNFR2, activated by paracrine mTNF, interacts with TRAF2, which is complex with TRAF3-NIK and c-IAP. TRAF2 is also associated with Parkin/PINK1 on the mitochondrial outer membrane. cIAP ubiquitinates TRAF2 by K63-linked ubiquitin chains, which stimulates the recruitment of LUBAC-OTULIN and TAK1. LUBAC adds M1-linked ubiquitin chains, resulting in the formation of mixed K63-linked and M1-linked ubiquitin chains, which is required to recruit NEMO. Subsequent phosphorylation of NEMO- associated IKKα and IKKβ by TAK1 activates the NF-κB signaling pathway, which starts the transcription of a large number of genes, required for neuronal survival. Furthermore, the formation of the NEMO-IKKα-IKKβ complex is necessary to phosphorylate and inhibit NIK. (B). Activated microglia secretes microvesicle (MV), which contain transmembrane TNF (tmTNF). The latter interacts with TNFR2, enforcing the endocytosis of the ligand-receptor complex to the perinuclear area. Cytoplasmic TNFR2-associated TRAF2-cIAP-TRAF3-NIK meets with Ubc6 and the E2 conjugating enzyme for c-IAP at the endoplasmic membrane. cIAP ubiquitination with K48-linked ubiquitin chains promotes the degradation of TRAF2 and TRAF3, leading to NIK accumulation. NIK phosphorylates IKKα for the initiation of the noncanonical NF-κB signaling pathway. In addition, NIK phosphorylates Drp1, which facilitates Drp1-PGAM5 interaction, and thus triggers mitochondrial fission. Oxidative stress caused by mitochondrial fission or NIK itself phosphorylates c-Abl at threonine 735 (T735).Activated c-Abl phosphorylates α-synuclein and tau, stimulating their aggregate formation. Parkin's functions are inhibited by c-Abl phosphorylation. The stimulatory phosphorylation of PARIS contributes to mitochondrial abnormalities. Finally, phosphorylation of OTULIN disrupts its association with LUBAC, facilitating the interaction of CYLD and LUBAC. Black arrows for stimulation; blocked red arrows for inhibition and blue arrows for activation signals.
References
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