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1.
mBio ; 12(1)2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33563842

RESUMO

In filamentous fungi, NLR-based signalosomes activate downstream membrane-targeting cell death-inducing proteins by a mechanism of amyloid templating. In the species Podospora anserina, two such signalosomes, NWD2/HET-S and FNT1/HELLF, have been described. An analogous system involving a distinct amyloid signaling motif, termed PP, was also identified in the genome of the species Chaetomium globosum and studied using heterologous expression in Podospora anserina The PP motif bears resemblance to the RIP homotypic interaction motif (RHIM) and to RHIM-like motifs controlling necroptosis in mammals and innate immunity in flies. We identify here a third NLR signalosome in Podospora anserina comprising a PP motif and organized as a two-gene cluster encoding an NLR and an HELL domain cell death execution protein termed HELLP. We show that the PP motif region of HELLP forms a prion we term [π] and that [π] prions trigger the cell death-inducing activity of full-length HELLP. We detect no prion cross-seeding between HET-S, HELLF, and HELLP amyloid motifs. In addition, we find that, like PP motifs, RHIMs from human RIP1 and RIP3 kinases are able to form prions in Podospora and that [π] and [Rhim] prions partially cross-seed. Our study shows that Podospora anserina displays three independent cell death-inducing amyloid signalosomes. Based on the described functional similarity between RHIM and PP, it appears likely that these amyloid motifs constitute evolutionarily related cell death signaling modules.IMPORTANCE Amyloids are ß-sheet-rich protein polymers that can be pathological or display a variety of biological roles. In filamentous fungi, specific immune receptors activate programmed cell death execution proteins through a process of amyloid templating akin to prion propagation. Among these fungal amyloid signaling sequences, the PP motif stands out because it shows similarity to the RHIM, an amyloid sequence controlling necroptotic cell death in mammals. We characterized an amyloid signaling system comprising a PP motif in the model species Podospora anserina, thus bringing to three the number of independent amyloid signaling cell death pathways described in that species. We then showed that human RHIMs not only propagate as prions in P. anserina but also partially cross-seed with fungal PP prions. These results indicate that, in addition to showing sequence similarity, the PP and RHIM motifs are at least partially functionally related, supporting a model of long-term evolutionary conservation of amyloid signaling mechanisms from fungi to mammals.


Assuntos
Amiloide/metabolismo , Chaetomium/fisiologia , Motivos de Nucleotídeos , Podospora/fisiologia , Príons/genética , Príons/fisiologia , Transdução de Sinais/genética , Amiloide/genética , Animais , Chaetomium/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/farmacocinética , Humanos , Mamíferos/genética , Mamíferos/metabolismo , Família Multigênica , Podospora/genética , Príons/classificação , Transdução de Sinais/fisiologia
2.
J Mol Biol ; 432(23): 6005-6027, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33058872

RESUMO

In filamentous fungi, amyloid signaling sequences allow Nod-like receptors (NLRs) to activate downstream cell-death inducing proteins with HeLo and HeLo-like (HELL) domains and amyloid RHIM and RHIM-related motifs control immune defense pathways in mammals and flies. Herein, we show bioinformatically that analogous amyloid signaling motifs exist in bacteria. These short motifs are found at the N terminus of NLRs and at the C terminus of proteins with a domain we term BELL. The corresponding NLR and BELL proteins are encoded by adjacent genes. We identify 10 families of such bacterial amyloid signaling sequences (BASS), one of which (BASS3) is homologous to RHIM and a fungal amyloid motif termed PP. BASS motifs occur nearly exclusively in bacteria forming multicellular structures (mainly in Actinobacteria and Cyanobacteria). We analyze experimentally a subset of seven of these motifs (from the most common BASS1 family and the RHIM-related BASS3 family) and find that these sequences form fibrils in vitro. Using a fungal in vivo model, we show that all tested BASS-motifs form prions and that the NLR-side motifs seed prion-formation of the corresponding BELL-side motif. We find that BASS3 motifs show partial prion cross-seeding with mammalian RHIM and fungal PP-motifs and that proline mutations on key positions of the BASS3 core motif, conserved in RHIM and PP-motifs, abolish prion formation. This work expands the paradigm of prion amyloid signaling to multicellular prokaryotes and suggests a long-term evolutionary conservation of these motifs from bacteria, to fungi and animals.


Assuntos
Amiloide/genética , Evolução Molecular , Imunidade Inata/genética , Proteínas NLR/genética , Motivos de Aminoácidos/genética , Sequência de Aminoácidos/genética , Proteínas Amiloidogênicas/genética , Animais , Cianobactérias/genética , Drosophila/genética , Fungos/genética , Genoma Bacteriano/genética , Príons/genética , Transdução de Sinais/genética
3.
Spine (Phila Pa 1976) ; 31(6): 705-11, 2006 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-16540877

RESUMO

STUDY DESIGN: We have retrospectively reviewed 11 chronic hemodialysis patients with cervical destructive spondyloarthropathy responsible for neural impairment 1 year after surgery and at last follow-up. OBJECTIVE: To evaluate clinical and radiologic outcomes, and necessity of vertebral block excision. SUMMARY OF BACKGROUND DATA: Destructive spondyloarthropathy of the cervical spine is associated with long-term hemodialysis for chronic kidney failure. Spinal cord compression and neurologic troubles occur in a few cases. Surgical treatment remains controversial because these are debilitated patients with multiple organ failures. METHODS: All 11 patients had unstable cervical spondylolisthesis, and 10 had kyphotic vertebral fusion involving at least 2 vertebrae. We performed interbody bone grafting (cement in 1 case) and stabilized with a plate. In 6 of the 10 patients with vertebral block, excision of the block was performed. RESULTS: No patients were lost to follow-up. One patient died 2 days after the operation. There were 2 other patients who required early surgical revision (i.e., a corporectomy followed by early graft expulsion). Bone healing settled in all patients. One year after surgery, patients had almost complete resolution of the pain and satisfactory neurologic recovery. Improvement was evaluated according to the Nurick classification. CONCLUSION: Functional and neurologic results were similar whether the patients did or did not undergo vertebral block excision, suggesting that stabilizing the unstable level may be sufficient in patients with neurologic impairment. Excision of spontaneous vertebral blocks should be avoided to minimize the morbidity of surgery in these debilitated patients with a limited life expectancy.


Assuntos
Vértebras Cervicais/cirurgia , Diálise Renal , Espondiloartropatias/cirurgia , Idoso , Placas Ósseas , Vértebras Cervicais/diagnóstico por imagem , Seguimentos , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/diagnóstico por imagem , Falência Renal Crônica/cirurgia , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/complicações , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/cirurgia , Radiografia , Estudos Retrospectivos , Fusão Vertebral , Espondiloartropatias/complicações , Espondiloartropatias/diagnóstico por imagem
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