Human RBM3 protein is prone to form neuronal aggregates opposed by the proteasome

TL;DR

The human RBM3 protein forms aggregates in neurons under cold conditions, and these aggregates are normally prevented by the proteasome system.

Contribution

This study reveals that human RBM3 forms cold-induced aggregates in neurons, distinct from stress granules and counteracted by the proteasome.

Findings

Human RBM3 forms aggregates in neurons under hypothermic conditions.

These aggregates are distinct from stress granules and occur specifically in differentiated neurons.

Proteasomal inhibition leads to RBM3 aggregation even at physiological temperatures.

Abstract

Maintenance of proteostasis is critical for neuronal functions, as the accumulation of misfolded or damaged proteins leads to neurodegeneration. Cooling is generally neuroprotective and is used in various clinical settings. However, how it impacts neuronal proteostasis remains unclear. In rodents, the neuroprotective effects of cold have been largely attributed to the cold-inducible RNA-binding motif protein 3 (RBM3). Here, studying the human RBM3 in cultured neurons subjected to profound hypothermia, we observed its cold-induced aggregation. These RBM3 aggregates are distinct from stress granules, occur specifically in differentiated neurons, and form also at physiological temperature upon proteasomal inhibition. Thus, in humans, RBM3 aggregation may be normally counteracted by the proteasome to maintain neuronal health. Exploring the natural variation between RBM3 proteins in hibernating versus non-hibernating mammals, we discuss how the aggregation could be prevented in animals with fluctuating body temperature. These findings are important for the understanding of RBM3 functions and neuronal proteostasis and have implications for medical treatments involving incidental and induced hypothermia.

Summary: RBM3 is a cold-inducible protein with neuroprotective functions in rodents. Here, we report cold-induced aggregation of the human RBM3 and discuss its implications for animal physiology.

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