PNMA2 forms immunogenic non-enveloped virus-like capsids associated with paraneoplastic neurological syndrome.

The paraneoplastic Ma antigen (PNMA) proteins are associated with cancer-induced paraneoplastic syndromes that present with an autoimmune response and neurological symptoms. Why PNMA proteins are associated with this severe autoimmune disease is unclear. PNMA genes are predominantly expressed in the central nervous system and are ectopically expressed in some tumors. We show that PNMA2, which has been co-opted from a Ty3 retrotransposon, encodes a protein that is released from cells as non-enveloped virus-like capsids. Recombinant PNMA2 capsids injected into mice induce autoantibodies that preferentially bind external "spike" PNMA2 capsid epitopes, whereas a capsid-assembly-defective PNMA2 protein is not immunogenic. PNMA2 autoantibodies in cerebrospinal fluid of patients with anti-Ma2 paraneoplastic disease show similar preferential binding to spike capsid epitopes. PNMA2 capsid-injected mice develop learning and memory deficits. These observations suggest that PNMA2 capsids act as an extracellular antigen, capable of generating an autoimmune response that results in neurological deficits.

Intercellular Communication in the Nervous System Goes Viral.

Viruses and transposable elements are major drivers of evolution and make up over half the sequences in the human genome. In some cases, these elements are co-opted to perform biological functions for the host. Recent studies made the surprising observation that the neuronal gene Arc forms virus-like protein capsids that can transfer RNA between neurons to mediate a novel intercellular communication pathway. Phylogenetic analyses showed that mammalian Arc is derived from an ancient retrotransposon of the Ty3/gypsy family and contains homology to the retroviral Gag polyproteins. The Drosophila Arc homologs, which are independently derived from the same family of retrotransposons, also mediate cell-to-cell signaling of RNA at the neuromuscular junction; a striking example of convergent evolution. Here we propose an Arc 'life cycle', based on what is known about retroviral Gag, and discuss how elucidating these biological processes may lead to novel insights into brain plasticity and memory.

Targeting the motor regulator Klar to lipid droplets.

BACKGROUND: In Drosophila, the transport regulator Klar displays tissue-specific localization: In photoreceptors, it is abundant on the nuclear envelope; in early embryos, it is absent from nuclei, but instead present on lipid droplets. Differential targeting of Klar appears to be due to isoform variation. Droplet targeting, in particular, has been suggested to occur via a variant C-terminal region, the LD domain. Although the LD domain is necessary and sufficient for droplet targeting in cultured cells, lack of specific reagents had made it previously impossible to analyze its role in vivo. RESULTS: Here we describe a new mutant allele of klar with a lesion specifically in the LD domain; this lesion abolishes both droplet localization of Klar and the ability of Klar to regulate droplet motion. It does not disrupt Klar's function for nuclear migration in photoreceptors. Using a GFP-LD fusion, we show that the LD domain is not only necessary but also sufficient for droplet targeting in vivo; it mediates droplet targeting in embryos, in ovaries, and in a number of somatic tissues. CONCLUSIONS: Our analysis demonstrates that droplet targeting of Klar occurs via a cis-acting sequence and generates a new tool for monitoring lipid droplets in living tissues of Drosophila.