PNMA2 forms immunogenic non-enveloped virus-like capsids associated with paraneoplastic neurological syndrome
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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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Cell |
| Vol/bind | 187 |
| Udgave nummer | 4 |
| Sider (fra-til) | 831-845.e19 |
| ISSN | 0092-8674 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
We thank Wesley Sundquist, John McCullough, and Ben Schmitz (Department of Biochemistry, University of Utah); Ryan M O'Connell, William Tang, and Warren Voth (Department of Pathology, University of Utah); John E. Greenlee and Noel G. Carlson (Department of Neurology, University of Utah and George E Wahlen VA Medical Center) for helpful discussions and experimental support. We thank Moriel Zelikowsky (Department of Neurobiology, University of Utah) for support and discussions on fear conditioning experiments. We thank the Hind laboratory (Department of Chemical and Biological Engineering, University of Colorado, Boulder) for providing the Luminex machine. We thank all members of the Shepherd lab for technical help and support. The graphic abstract was created with BioRender.com. S.E. was supported by the Novo Nordisk Foundation (NNF17OC0030788); G.A.H. by NIH T32 CA174648; A.M.W. by NIH R01 NS131660 and the ALS Association; C.F. by NIH R35 GM122550; J.A.G.B. by the Max Planck Society and Medical Research Council (MC_UP_1201/16); J.D.S. by NIH R01 NS115716, the Chan-Zuckerberg Initiative Ben Barres Early Acceleration Award, the Brain Research Foundation Scientific Innovation Award, and the Jon M. Huntsman Presidential Endowed Chair fund. J.X. performed the biochemistry, electron microscopy, ELISA, RNAscope, immunohistochemistry, mice immunization, and behavior experiments. S.E. conducted the cryo-EM experiments and structure determination. M.S. performed phylogenetic and RNA-seq analysis. M.R. conducted RNAscope, mice immunization, blood collection and helped with behavior experiments. G.A.H. performed the in vitro dendritic cell activation and cytokine assays. I.I. performed mass photometry experiments. J.E. and M.H. generated rat primary cultured neurons. G.S.D. A.L.P. T.L.S. and S.L.C. provided the clinical human samples. J.X. S.E. M.S. G.A.H. M.R. A.M.W. C.F. J.A.G.B. and J.D.S. conceived and designed experiments. J.X. and J.D.S. wrote the manuscript; all authors discussed results and edited the manuscript. C.F. is a consultant for Tessera Therapeutics, Inc. and HAYA Therapeutics, Inc. J.D.S. is a co-founder of VNV, LLC and holds stock in and is a consultant for Aera Therapeutics, Inc. which licenses intellectual property and patents that include PNMA proteins.
Funding Information:
S.E. was supported by the Novo Nordisk Foundation ( NNF17OC0030788 ); G.A.H. by NIH T32 CA174648 ; A.M.W. by NIH R01 NS131660 and the ALS Association ; C.F. by NIH R35 GM122550 ; J.A.G.B. by the Max Planck Society and Medical Research Council ( MC_UP_1201/16 ); J.D.S. by NIH R01 NS115716 , the Chan-Zuckerberg Initiative Ben Barres Early Acceleration Award , the Brain Research Foundation Scientific Innovation Award , and the Jon M. Huntsman Presidential Endowed Chair fund .
Publisher Copyright:
© 2024 Elsevier Inc.
ID: 384618483