PNMA2 forms non-enveloped virus-like capsids that trigger paraneoplastic neurological syndrome

Abstract

Theparaneoplastic Ma antigen (PNMA)genes are associated with cancer-induced paraneoplastic syndromes that present with neurological symptoms and autoantibody production. How PNMA proteins trigger a severe autoimmune disease is unclear.PNMAgenes are predominately expressed in the central nervous system with little known functions but are ectopically expressed in some tumors. Here, we show that PNMA2 is derived from a Ty3 retrotransposon that encodes a protein which forms virus-like capsids released from cells as non-enveloped particles. Recombinant PNMA2 capsids injected into mice induce a robust autoimmune reaction with significant generation of autoantibodies that preferentially bind externalspikePNMA2 capsid epitopes, while capsid-assembly-defective PNMA2 protein is not immunogenic. PNMA2 autoantibodies present in cerebrospinal fluid of patients with anti-Ma2 paraneoplastic neurologic disease show similar preferential binding to PNMA2spikecapsid epitopes. These observations suggest that PNMA2 capsids released from tumors trigger an autoimmune response that underlies Ma2 paraneoplastic neurological syndrome.

The diverse evolutionary histories of domesticated metaviral capsid genes in mammals

“…For example, the PNMA gene family is so named because PNMA1 encodes a protein associated with the autoimmune disorder paraneoplastic syndrome (PNMA1: paraneoplastic Ma antigen 1). Other PNMA genes may have similar phenotypes, although it is unclear currently whether their autoimmune consequences are related to their endogenous function or irregular expression or regulation (Dalmau et al 1999; Schüller et al 2005; Henry 2019; Xu et al 2023). Little is known about the endogenous cellular function of the PNMA family genes.…”

“…Brandt et al 2005; Campillos et al 2006; Ono et al 2006; Sekita et al 2008; Kokošar and Kordiš 2013). At least four domesticated capsid genes have been shown to assemble into capsid-like structures (Pastuzyn et al 2018; Abed et al 2019; Erlendsson et al 2019; Segel et al 2021; Xu et al 2023), which perform essential functions in host reproduction (Ono et al 2006) and neuronal function (Nikolaienko et al 2018; Pastuzyn et al 2018). One of these gag- derived genes is vertebrate Arc (A ctivity- R egulated, C ytoskeletal-associated), which originated from an ancient retroelement from the clade Metaviridae (formerly known as Ty3/Gypsy).…”

“…Together, Arc and dArc1 elegantly demonstrate the functional convergence of independently domesticated genes in animal lineages. Although other domesticated gag genes also encode proteins capable of assembling into capsid-like structures, most remain functionally uncharacterized (Xu et al 2023).…”

Birth of protein-coding exons by ancient domestication of LINE retrotransposon

“…For example, Syncytin proteins encoded by env genes of endogenous retroviruses (ERVs) contribute to trophoblast cell fusion and immunosuppression in the mammalian placenta (3, 4). The gag genes encoding virus-like capsid proteins of long terminal repeat (LTR) retrotransposons are also co-opted as host genes: ARC for synaptic plasticity (5, 6), Peg10 and Rtl1 for placenta formation (7, 8), and PNMA2 expressed in neurons and related with autoimmune diseases (9). Other examples include ASPRV1/SASPase , derived from a retroviral protease involved in the protease activity for mammalian skin formation (10); NYNRIN , derived from integrase and contributing to placentation (11); and RTOM family, derived from reverse transcriptase in monotremes (12).…”

Human paraneoplastic antigen Ma2 (PNMA2) forms icosahedral capsids that can be engineered for mRNA delivery

“…Although several PNMA family members have been previously reported to have roles in apoptosis ( 12 – 16 ), most remain poorly characterized. Some PNMAs, however, including mouse PNMA2, have been shown to form capsid structures, suggesting they may be suitable for development as delivery vehicles ( 6 , 17 ).…”