Targeting the paralog encoded protein for degradation accounts for the opposite roles of NRBP1 and NRBP2 in regulating LINE1 retrotransposition

ABSTRACT: The activation of Long Interspersed Nuclear Element 1 (LINE1/L1) retrotransposons not only leads to genome instability, a factor associated with the development of human diseases, but also plays crucial biological roles in fostering genetic diversity and neuronal functions. Therefore, investigating the regulatory mechanisms that have co-evolved to enable the context-dependent activation or suppression of L1 is important for comprehending pathogenesis associated with aberrant L1 activity. Here we show that two paralogs encoding the pseudokinases NRBP1 and NRBP2 oppositely regulate L1 retrotransposon, via influencing integrity of the L1 ribonucleoprotein complex. We demonstrate that the antagonism between NRBP1 and NRBP2 is not a result of the competitive mechanism, but rather due to targeting NRBP1 to proteasome-mediated degradation by NRBP2, probably through heterodimer formation between these two closely related proteins. In addition, we show that reduced NRBP2 activity is correlated with elevated innate immune response and occurrence of autoimmune diseases, which could also be induced upon L1 activation. Moreover, our phylogenetic analysis suggests NRBP2gene as a duplication of the ancestral NRBP, indicating that evolutionary pressure has favoured this acquired layer of functional fine-tuning of the precursor gene. In summary, our discovery not only identifies NRBP1 and NRBP2 as novel L1 regulators and implicates their involvement in human pathogenesis, but also provides novel insights into the regulatory details arising from gene duplication events.

INSTRUMENT(S): LTQ Orbitrap XL, LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Jennifer Schwarz  

LAB HEAD: Ralf Baumeister

PROVIDER: PXD051452 | Pride | 2025-06-07

REPOSITORIES: Pride