UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome

Abstract

SummaryClearance of misfolded and aggregated proteins is central to cell survival. Here, we describe a new pathway for maintaining protein homeostasis mediated by the proteasome shuttle factor UBQLN2. The 26S proteasome degrades polyubiquitylated substrates by recognizing them through stoichiometrically bound ubiquitin receptors, but substrates are also delivered by reversibly bound shuttles. We aimed to determine why these parallel delivery mechanisms exist and found that UBQLN2 acts with the HSP70-HSP110 disaggregase machinery to clear protein aggregates via the 26S proteasome. UBQLN2 recognizes client-bound HSP70 and links it to the proteasome to allow for the degradation of aggregated and misfolded proteins. We further show that this process is active in the cell nucleus, where another system for aggregate clearance, autophagy, does not act. Finally, we found that mutations in UBQLN2, which lead to neurodegeneration in humans, are defective in chaperone binding, impair aggregate clearance, and cause cognitive deficits in mice.

Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS–FTD-linked UBQLN2 mutations

“…In contrast with our results, other rodent models expressing the ALS-FTD-linked P497H or P506T UBQLN2 mutation developed only cognitive, but not motor neuron disease (19,27,29). The reason for the difference is not clear.…”

“…One likely possibility is that the level of mtUBQLN2 expression required to induce motor neuron disease needs to be higher than was achieved in the other rodent models. In one of these models, the same P506T UBQLN2 mutation carried by one of our models was knocked in at an equivalent position in the mouse UBQLN2 gene, yet those mice did not develop motor neuron disease (19). This would suggest that the mouse UBQLN2 gene is either expressed at lower levels than in humans and/or that despite their similar expression, the very short lifespan of mice compared with humans is insufficient for motor neuron disease to manifest.…”

“…In both lines UBQLN puncta were found in the hippocampus in a pattern similar to that seen in humans carrying UBQLN2 mutations. A P520T knockin mouse model, carrying the equivalent P506T UBQLN2 mutation in humans, developed cognitive deficits and UBQLN2 inclusions in the brain, but did not develop motor neuron disease (19). Other studies showed that mice injected with adeno-associated virus (AAV) expressing the P497S and P506T UBQLN2 mutations perform worse on the rotarod than mice expressing WT UBQLN2 or the P497H mutation (31).…”

“…On the other hand, it could signify a loss of function, because UBQLN proteins function in autophagy, which typically involves clearance of large aggregates. Other studies have shown ALS-FTD UBQLN2 mutations reduce binding of UBQLN2 with its normal partners, suggesting a possible loss of function (19,22,28). Evidently, understanding how UBQLN2 mutations cause ALS-FTD is important for understanding the mechanisms underlying the disease and for developing novel pharmacotherapies to halt the disease.…”

“…Additional UBQLN2 mutations have now been identified, and interestingly, like the original mutations, encode missense mutations in the central domain of UBQLN2 protein (14-16). The function of the central domain of UBQLN2 is beginning to emerge with studies showing it assists in chaperone function (17)(18)(19) and in docking the protein with different adaptors of its function (20)(21)(22). The function of the two end domains that border the central domain is better understood.…”