iBET & ITQB researchers involved in uncovering a new role for RuvBL1/RuvBL2

Researchers from the Industry and Medicine Applied Crystallography Lab (ITQB) and the Structural Biology for Drug Discovery Unit (iBET) collaborated with an international team led by Dr. Michael Y Sherman (Boston University School of Medicine) in the discovery of a new role for proteins RuvBL1 (also known as Pontin) and RuvBL2 (also known as Reptin) leading to a research article recently published in the EMBO Journal. RuvBL1 and RuvBL2 are highly conserved eukaryotic proteins belonging to the AAA+ family of ATPases, and closely related to the bacterial DNA helicase RuvB. RuvBL1 (also known as Pontin and Tip49), and RuvBL2 (also known as Reptin and Tip48) are ubiquitously expressed and have been associated with cellular functions such as transcription, cellular transformation, mitosis and others. These proteins are known to participate in large molecular complexes such as the INO80, TIP60 or R2TP complexes, involved in chromatin remodeling, DNA damage repair and pre-RNA processing. In the last decade, a link between RuvBL1, RuvBL2 and cancer was established. Both proteins interact with transcription regulators known to be involved in oncogenic pathways. Among the transcription factors with oncogenic potential, c-Myc is one of the most frequent sites of mutation in human cancer. The study by Sherman and collaborators revealed yet another role for these multirole proteins, as chaperones on protein disaggregation. The aggresome is an organelle that recruits aggregated proteins for storage and degradation. An siRNA screen for proteins involved in aggresome formation identified RuvBL1 and RuvBL2 as novel protein disaggregases. Depletion of these two proteins suppressed aggresome formation and caused buildup of cytoplasmic aggregates and a similar behavior was observed in yeast. In contrast, overproduction of RuvBL1 and RuvBL2 enhanced cell resistance to proteotoxic stress, independently of chaperone Hsp104. Also, the ATPase activity of the RuvBL proteins was stimulated by polypeptides with unfolded structures and amyloid fibrils. The body of experimental data indicates that RuvBL1/RuvBL2 complexes serve as chaperones in protein disaggregation.  
Original Article RuvbL1 and RuvbL2 enhance aggresome formation and disaggregate amyloid fibrils. Zaarur N, Xu X, Lestienne P, Meriin AB, McComb M, Costello CE, Newnam GP, Ganti R, Romanova NV, Shanmugasundaram M, Silva ST, Bandeiras TM, Matias PM, Lobachev KS, Lednev IK, Chernoff YO, Sherman MY. EMBO J. 2015 Aug 24. pii: e201591245.