A lysine-to-arginine change found in natural alleles of the human T-cell lymphotropic leukemia virus type 1 p12 protein greatly influences its stability

The HTLV-1 singly spliced open reading frame I protein, p12(I), is highly u nstable and appears to be necessary for persistent infection in rabbits. He re we demonstrate that p12(I) forms dimers through two putative leucine zip per domains and that its stability is augmented by specific proteasome inhi bitors. p12(I) is ubiquitylated, and mutations of its unique carboxy-termin us lysine residue to an arginine greatly enhance its stability. Interesting ly, analysis of 53 independent HTLV-1 strains revealed that the natural p12 (I) alleles found in ex vivo samples of tropical spastic paraparesis-HTLV-1 -associated myelopathy patients contain a Lys at position 88 in some cases, whereas arginine is consistently found at position 88 in HTLV-1 strains fr om all adult T-cell leukemia-lymphoma (ATLL) cases and healthy carriers stu died. This apparent segregation of different alleles in tropical spastic pa raparesis-HTLV-associated myelopathy and ATLL or healthy carriers may be re levant in vivo, since p12(I) binds the interleukin-2 receptor beta and gamm a(c) chains, raising the possibility that the two natural alleles might aff ect differently the regulation of these molecules.