Global Proteotoxicity Caused by Human β2 Microglobulin Variants Impairs the Unfolded Protein Response in C. elegans

Abstract

Aggregation of β2 microglobulin (β2m) into amyloid fibrils is associated with systemic amyloidosis, caused by the deposition of amyloid fibrils containing the wild-type protein and its truncated variant, ΔN6 β2m, in haemo-dialysed patients. A second form of familial systemic amyloidosis caused by the β2m variant, D76N, results in amyloid deposits in the viscera, without renal dysfunction. Although the folding and misfolding mechanisms of β2 microglobulin have been widely studied in vitro and in vivo, we lack a comparable understanding of the molecular mechanisms underlying toxicity in a cellular and organismal environment. Here, we established transgenic C. elegans lines expressing wild-type (WT) human β2m, or the two highly amyloidogenic naturally occurring variants, D76N β2m and ΔN6 β2m, in the C. elegans bodywall muscle. Nematodes expressing the D76N β2m and ΔN6 β2m variants exhibit increased age-dependent and cell nonautonomous proteotoxicity associated with reduced motility, delayed development and shortened lifespan. Both β2m variants cause widespread endogenous protein aggregation contributing to the increased toxicity in aged animals. We show that expression of β2m reduces the capacity of C. elegans to cope with heat and endoplasmic reticulum (ER) stress, correlating with a deficiency to upregulate BiP/hsp-4 transcripts in response to ER stress in young adult animals. Interestingly, protein secretion in all β2m variants is reduced, despite the presence of the natural signal sequence, suggesting a possible link between organismal β2m toxicity and a disrupted ER secretory metabolism.