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

Abstract

<jats:p>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.</jats:p>

Human endogenous retrovirus K (HERV-K) env in neuronal extracellular vesicles: a new biomarker of motor neuron disease

“…Li et al (16) found that both HERV-K env transgenic cells and mice showed ALS-like neurological symptoms and pathological manifestations. Arru et al (29) detected a significant increase in anti-HERV-K env-su [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] IgG antibodies in the serum and cerebrospinal fluid of ALS patients, suggesting that a humoral immune response to HERV-K env occurred in ALS patients. It is speculated that HERV-K env plays a role in the pathogenesis and progression of MND.…”

The role of IFN-γ production during retroviral infections: an important cytokine involved in chronic inflammation and pathogenesis

“…Bioinformatic analysis suggested that the viral promoter of ERVK is responsive to inflammatory transcription factors 54 . For example, ERVK upregulation in amyotrophic lateral sclerosis (ALS) is the presence of functional interferon-stimulated response elements (ISREs) in the viral promoter 55 . Transcription factor overexpression assays revealed independent and synergistic upregulation of ERVK by interferon regulatory factor 1 (IRF1) and NF-κB isoforms.…”

Transposable Elements in Pluripotent Stem Cells and Human Disease

“…In fact, the inhibition of HERV-K expression with anti-viral therapy decelerated ALS progression ( Arru et al, 2018 ). Interestingly, one study identified a conotoxin-like protein that was produced from an ERVK sequence as a potential factor in ALS neuropathology ( Curzio et al, 2020 ). The conotoxin-like protein could induce NF-kB pro-inflammatory signaling, and its presence was linked with regions of damage in ALS samples ( Curzio et al, 2020 ).…”

“…Interestingly, one study identified a conotoxin-like protein that was produced from an ERVK sequence as a potential factor in ALS neuropathology ( Curzio et al, 2020 ). The conotoxin-like protein could induce NF-kB pro-inflammatory signaling, and its presence was linked with regions of damage in ALS samples ( Curzio et al, 2020 ). Other studies have also documented various ways in which ERVs potentially contribute to multiple sclerosis ( Perron et al, 1997 ; Antony et al, 2007 ).…”