Amyotrophic Lateral Sclerosis (ALS) is a fatal, neurodegenerative disease characterized by progressive motor neuron dysfunction and loss. A portion of ALS is caused by mutation of the proteasome shuttle factor Ubiquilin 2 (UBQLN2), but the molecular pathway leading from UBQLN2 dysfunction to disease remains unclear. Here, we demonstrate a function of UBQLN2 in regulating activity of the domesticated gag-pol retrotransposon 'paternally expressed gene 10' (PEG10) in human cells and tissues. In cells, the PEG10 gag-pol protein cleaves itself in a mechanism reminiscent of retrotransposon self-processing to generate a liberated 'nucleocapsid' fragment, which uniquely localizes to the nucleus and changes expression of genes involved in axon remodeling. In spinal cord tissue from ALS patients, PEG10 gag-pol is elevated compared to healthy controls. These findings implicate the retrotransposon-like activity of PEG10 as a contributing mechanism in ALS through regulation of gene expression, and restraint of PEG10 as a primary function of UBQLN2.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron dysfunction and loss. A portion of ALS cases are caused by mutation of the proteasome shuttle factor Ubiquilin 2 (UBQLN2), but the molecular pathway leading from UBQLN2 dysfunction to disease remains unclear. Here, we demonstrate that UBQLN2 regulates the domesticated gag-pol retrotransposon 'paternally expressed gene 10' (PEG10) in human cells and tissues. In cells, the PEG10 gag-pol protein cleaves itself in a mechanism reminiscent of retrotransposon self-processing to generate a liberated 'nucleocapsid' fragment, which uniquely localizes to the nucleus and changes the expression of genes involved in axon remodeling. In spinal cord tissue from ALS patients, PEG10 gag-pol is elevated compared to healthy controls. These findings implicate the retrotransposon-like activity of PEG10 as a contributing mechanism in ALS through regulation of gene expression, and restraint of PEG10 as a primary function of UBQLN2.

Transposable elements can cause catastrophic genomic instability and are tightly regulated by the host through multiple restriction pathways. Domesticated elements are derived from these ancestors and have evolved adaptive roles but may retain pathological activity. For example, PEG10 is required for placentation but also promotes cancer and neurodegeneration. While much of PEG10 remains poorly understood, a unique feature is its ability to readily form virus-like particles (VLPs) which may contribute to its adaptive and pathological nature. However, comparable restriction networks that antagonize the harmful potential of domesticated genes like PEG10 remain unknown. Here, we describe restriction of PEG10 VLP abundance via UBQLN2 and the domesticated retrotransposon RTL8. The gag-like RTL8 antagonizes PEG10 through competitive incorporation into VLPs reminiscent of transposable element inhibitors from diverse eukaryotes. These results represent the first known instance of a retroelement-derived restriction factor antagonizing another domesticated retrotransposon and have implications for our understanding of PEG10 biology.

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