Pro-Inflammatory Signaling Upregulates a Neurotoxic Conotoxin-Like Protein Encrypted Within Human Endogenous Retrovirus-K.

Autor: Curzio DD; Department of Biology, University of Winnipeg, 599 Portage Avenue, Winnipeg, MB R3B 2G3, Canada., Gurm M; Department of Biology, University of Winnipeg, 599 Portage Avenue, Winnipeg, MB R3B 2G3, Canada.; Department of Immunology, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB R3E 0T5, Canada., Turnbull M; Department of Biology, University of Winnipeg, 599 Portage Avenue, Winnipeg, MB R3B 2G3, Canada., Nadeau MJ; Department of Biology, University of Winnipeg, 599 Portage Avenue, Winnipeg, MB R3B 2G3, Canada., Meek B; Department of Biology, University of Winnipeg, 599 Portage Avenue, Winnipeg, MB R3B 2G3, Canada., Rempel JD; Department of Biology, University of Winnipeg, 599 Portage Avenue, Winnipeg, MB R3B 2G3, Canada., Fineblit S; Department of Biology, University of Winnipeg, 599 Portage Avenue, Winnipeg, MB R3B 2G3, Canada., Jonasson M; Department of Biology, University of Winnipeg, 599 Portage Avenue, Winnipeg, MB R3B 2G3, Canada., Hebert S; Department of Biology, University of Winnipeg, 599 Portage Avenue, Winnipeg, MB R3B 2G3, Canada., Ferguson-Parry J; Department of Biology, University of Winnipeg, 599 Portage Avenue, Winnipeg, MB R3B 2G3, Canada., Douville RN; Department of Biology, University of Winnipeg, 599 Portage Avenue, Winnipeg, MB R3B 2G3, Canada.; Department of Immunology, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB R3E 0T5, Canada.
Jazyk: angličtina
Zdroj: Cells [Cells] 2020 Jun 30; Vol. 9 (7). Date of Electronic Publication: 2020 Jun 30.
DOI: 10.3390/cells9071584
Abstrakt: Motor neuron degeneration and spinal cord demyelination are hallmark pathological events in Amyotrophic Lateral Sclerosis (ALS). Endogenous retrovirus-K (ERVK) expression has an established association with ALS neuropathology, with murine modeling pointing to a role for the ERVK envelope ( env ) gene in disease processes. Here, we describe a novel viral protein cryptically encoded within the ERVK env transcript, which resembles two distinct cysteine-rich neurotoxic proteins: conotoxin proteins found in marine snails and the Human Immunodeficiency Virus (HIV) Tat protein. Consistent with Nuclear factor-kappa B (NF-κB)-induced retrotransposon expression, the ERVK conotoxin-like protein (CTXLP) is induced by inflammatory signaling. CTXLP is found in the nucleus, impacting innate immune gene expression and NF-κB p65 activity. Using human autopsy specimens from patients with ALS, we further showcase CTXLP expression in degenerating motor cortex and spinal cord tissues, concomitant with inflammation linked pathways, including enhancement of necroptosis marker mixed lineage kinase domain-like (MLKL) protein and oligodendrocyte maturation/myelination inhibitor Nogo-A. These findings identify CTXLP as a novel ERVK protein product, which may act as an effector in ALS neuropathology.
Databáze: MEDLINE
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