Toll/Interleukin-1 Receptor Domain Dimers as the Platform for Activation and Enhanced Inhibition of Toll-like Receptor Signaling

Fekonja, Ota; Benčina, Mojca; Jerala, Roman

doi:10.1074/jbc.m112.376186

Cited by 28 publications

(35 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Tethered MyD88 WT TIR domains exhibit inhibition of TLR signaling at low expression levels but constitutive activity at higher expression levels. 22 We observed the similar dose-dependent response for lymphoma-associated MyD88 TIR-only constructs, namely inhibition of TLR4 signaling upon LPS stimulation at lower expression and increased activation at higher expression levels for the M232T, L265P, and V217F lymphomaassociated mutant ( Figure 1F). Thus, lymphoma-associated TIRdomain mutants display a phenotype similar to that of a forced dimer of WT TIR domains, suggesting that a di/oligomeric MyD88 TIRdomain platform is a prerequisite for the constitutive activation.…”

supporting

confidence: 49%

“…The isolated MyD88 wild-type (WT) TIR domain has a dominant-negative effect on TLR signaling, 6 but forced TIR domain dimerization, eg, based on the intrinsic affinity of TIR domains of TLR4 21 or tandem constructs of MyD88 TIR domains (tethered TIR domains), constitutively initiate signaling, suggesting that TIR di/oligomerization may initiate nucleation of Myddosomes in the absence of an incoming TLR signaling. 22 Whether and how these results relate to a physiologically relevant process has not been determined so far.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR-domain oligomerization

Avbelj

Wolz

Fekonja

et al. 2014

Blood

Self Cite

View full text Add to dashboard Cite

Key Points• The hyperactive phenotype of lymphoma-associated mutations is caused by increased oligomerization propensity of the MyD88 TIR domain.• The TIR domain of mutants interacts with wild-type MyD88, explaining why heterozygous mutation could be sufficient as a driver mutation.Myeloid differentiation 88 (MyD88) is the key signaling adapter of Toll-like and interleukin-1 receptors. Recurrent lymphoma-associated mutations, particularly Leu265Pro (L265P), within the MyD88 Toll/interleukin-1 receptor (TIR) domain sustain lymphoma cell survival due to constitutive nuclear factor kB signaling. We found that mutated TIR domains displayed an intrinsic propensity for augmented oligomerization and spontaneous formation of cytosolic Myddosome aggregates in lymphoma cell lines, mimicking the effect of dimerized TIR domains. Blocking of MyD88 oligomerization induced apoptosis. The L265P TIR domain can recruit the endogenous wild-type MyD88 for oligomer formation and hyperactivity. Molecular dynamics simulations and analysis of additional mutations suggest that constitutive activity is caused by allosteric oligomerization. (Blood. 2014;124(26):3896-3904) IntroductionMyeloid differentiation 88 (MyD88) is a pivotal signaling protein in the innate immune system, participating in Toll-like receptor (TLR) signaling pathways during a host's response to infection. 1 Patients with germline MYD88 loss-of-function mutations suffer from severe susceptibility to pyogenic bacterial infection during childhood and only survive into adulthood on a strict therapy of antibiotics.2 Conversely, somatic MyD88 gain-of-function mutations were recently discovered in diffuse large B-cell lymphoma (DBLCL), Waldenström's macroglobulinemia (WM), and chronic lymphocytic leukemia (supplemental Tables 1 and 2 available on the Blood Web site). These data suggest that such mutations, particularly the most prominent Leu265Pro (L265P) mutation, are oncogenic driver mutations that sustain B-cell survival and thus oncogenesis. Indeed, MyD88-mutated cells (cell lines and primary cells) could be selectively killed by ablation of MyD88 downstream signaling using short hairpin RNA or pharmacologic inhibition. 3,4 Although hyperactivation of nuclear factor kB (NF-kB) has been described as a key feature of MyD88-mutated B cells, the molecular mechanism of how the amino acid alterations in lymphomaassociated MyD88 mutations exert this phenotype has to be resolved.MyD88 is composed of an N-terminal death domain (DD) 5 and a highly conserved C-terminal Toll/interleukin-1 receptor (TIR) domain. 6 Whereas the DD and an intermediate linker domain 7 are responsible for downstream signal propagation via kinases of the interleukin-1 receptor-associated kinases (IRAKs), 8 the MyD88 TIR domain integrates signals from upstream TLR and interleukin-1 receptor. Association of TLRs mediated by their agonists triggers the formation of TIR-domain dimers, which results in downstream signaling and expression of genes involved in the host defense system. 1,9 TIR domains comprise 135-...

show abstract

supporting

confidence: 49%

Section: Introductionmentioning

confidence: 99%

Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR-domain oligomerization

Avbelj

Wolz

Fekonja

et al. 2014

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…1 B and C), indicating that exchanging one partner in the complex is sufficient to overcome the slower kinetics of CeTIR homodimers. We investigated the specificity of this phenomenon by evaluating the TIR domain from Myd88, which does not induce cell death as a homodimer (4,15,16). Enforced dimerization between HsTIR and the TIR domain from Myd88 did not induce cell death (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Enforced homodimerization of the human SARM1 TIR (HsTIR) domain stimulates rapid consumption of NAD + followed by axon degeneration and cell death (4). The capacity of dimerized SARM1 TIR to stimulate NAD + loss and cell death is unique, because dimerization of other human TIR domains does not induce axon degeneration or cell death (4,15,16). Hence, the TIR domain of SARM1 possesses distinct qualities that enable SARM1-dependent NAD + loss after neuronal injury.…”

mentioning

confidence: 99%

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Summers

Gibson

DiAntonio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

121

125

View full text Add to dashboard Cite

Axon injury in response to trauma or disease stimulates a selfdestruction program that promotes the localized clearance of damaged axon segments. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner of this degeneration cascade, also known as Wallerian degeneration; however, the mechanism of SARM1-dependent neuronal destruction is still obscure. SARM1 possesses a TIR domain that is necessary for SARM1 activity. In other proteins, dimerized TIR domains serve as scaffolds for innate immune signaling. In contrast, dimerization of the SARM1 TIR domain promotes consumption of the essential metabolite NAD + and induces neuronal destruction. This activity is unique to the SARM1 TIR domain, yet the structural elements that enable this activity are unknown. In this study, we identify fundamental properties of the SARM1 TIR domain that promote NAD + loss and axon degeneration. Dimerization of the TIR domain from the Caenorhabditis elegans SARM1 ortholog TIR-1 leads to NAD + loss and neuronal death, indicating these activities are an evolutionarily conserved feature of SARM1 function. Detailed analysis of sequence homology identifies canonical TIR motifs as well as a SARM1-specific (SS) loop that are required for NAD + loss and axon degeneration. Furthermore, we identify a residue in the SARM1 BB loop that is dispensable for TIR activity yet required for injury-induced activation of full-length SARM1, suggesting that SARM1 function requires multidomain interactions. Indeed, we identify a physical interaction between the autoinhibitory N terminus and the TIR domain of SARM1, revealing a previously unrecognized direct connection between these domains that we propose mediates autoinhibition and activation upon injury.A xon degeneration in response to injury or disease is a hallmark of neurological disorders of the peripheral and central nervous systems. Akin to programmed cell death pathways, such as apoptosis, axon injury in response to disease or trauma stimulates a local signaling cascade that executes destruction of the injured axon segment (1). Despite growing attention, the molecular details of this prodegenerative cascade are still unclear. A more substantial understanding of the molecular factors that participate in this axon destructive process will likely provide new therapeutic strategies for peripheral neuropathies and other neurodegenerative conditions.Genetic screens in invertebrate and vertebrate model systems identified the Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) as a conserved, fundamental executioner of pathological axon destruction (2, 3). After nerve injury, SARM1 is required for the precipitous loss of the metabolite NAD + (4). Augmenting NAD + biosynthetic pathways protects injured axons from degeneration, suggesting this step is crucial in axonal breakdown (5, 6). In addition to local axon degeneration, SARM1 promotes neuronal cell death in response to mitochondrial toxins, oxygen gluc...

show abstract

“…Furthermore, these studies provided novel insights into the structural interactions and function of TIR domains that could potentially augment the efficacy of TLR agonists and antagonists. Fekonja et al (2012b) showed that the addition of a strong-coiled coil dimerization domain determined the degree of inhibition against various TLRs and prevented activation of the dimeric TIR platform and Piao et al (2013a) identified TRIF sites that are important for interaction with TLR4 and TRAM. Intense interest in the BB loop of TIR domain has guided research efforts in the development of inhibitory peptides (Toshchakov et al, 2007(Toshchakov et al, , 2011Piao et al, 2013a).…”

Section: Novel Approaches For Targeting Toll-like Receptor Signalingmentioning

confidence: 99%

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

2015

View full text Add to dashboard Cite

Toll/Interleukin-1 Receptor Domain Dimers as the Platform for Activation and Enhanced Inhibition of Toll-like Receptor Signaling

Cited by 28 publications

References 41 publications

Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR-domain oligomerization

Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR-domain oligomerization

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

Contact Info

Product

Resources

About

Toll/Interleukin-1 Receptor Domain Dimers as the Platform for Activation and Enhanced Inhibition of Toll-like Receptor Signaling

Cited by 28 publications

References 41 publications

Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR-domain oligomerization

Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR-domain oligomerization

SARM1-specific motifs in the TIR domain enable NAD + loss and regulate injury-induced SARM1 activation

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

Contact Info

Product

Resources

About

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation