AMPK modulates a DEAH Box RNA-helicase to attenuate TOR signaling and establish developmental quiescence

Abstract

Developmental plasticity allows organisms to adapt to environmental stress and improve reproductive fitness. Caenorhabditis elegans adapts to starvation and other stressors by transiting through an alternate developmental stage called dauer, which allows them to remain quiescent for several months, and yet fully retain reproductive fitness when they resume development. The AMP-activated protein kinase (AMPK) is essential for this plasticity as its compromise leads to germline hyperplasia during the dauer stage, dramatically reducing post-dauer fertility upon recovery from this stage, while also shortening survival. We identified a putative RNA-binding helicase (HZL-1) that is targeted by AMPK, the compromise of which suppresses several AMPK mutant phenotypes. HZL-1 shares significant similarity with the conserved HELZ family of RNA helicases, possessing characteristic DEAH helicase motifs, a predicted ATP binding motif, and three intrinsically disordered regions that are crucial for its localization and function. Curiously, HZL-1 is expressed and exerts its function in the intestine, yet its elimination suppresses the aberrant germ cell proliferation, while restoring germline quiescence and subsequent post-dauer fertility. CLIP-seq data revealed that HZL-1 binds several mRNAs during the dauer stage, resulting in a pronounced germline hyperplasia in the dauer germ line of AMPK mutants. Among these, the most enriched RNA bound to HZL-1, argk-1, is required for fertility in HZL-1 mutants, and functions by suppressing TOR activity in the germ line of AMPK dauer larvae, thereby preserving germline quiescence. These findings underscore the intricate role of RNAs and RNA-binding helicases in the complex interplay of genetic signals that animals have acquired to ensure their effective transit through periods of environmental challenge.