Association of translation factor eEF1A with defective ribosomal products generates a signal for aggresome formation.

Abstract

Aggresome formation is initiated upon proteasome failure, and facilitates autophagic clearance of protein aggregates to protect cells from proteotoxicity. Here we demonstrate that proteasome inhibition generates a signaling event to trigger aggresome formation. In aggresome signaling, the cell senses a buildup of aberrant newly synthesized proteins. The translation elongation factor eEF1A associated with these species, and knockdown of this factor suppressed aggresome formation. We employed the Legionella toxin SidI to distinguish between the function of eEF1A in translation and its novel function in the aggresome formation. In fact, while strongly inhibiting translation, this toxin had only a marginal effect on aggresome formation. Furthermore, SidI reduced the threshold of the aberrant ribosomal products for triggering aggresome formation. Therefore, eEF1A binds defective polypeptides released from ribosomes, which generates a signal that triggers aggresome formation.