LONG-RANGE SIGNALING AT THE INTESTINAL-NEURAL AXIS PROMOTES ORGANISMAL HEME HOMEOSTASIS IN C. ELEGANS

Abstract

Metazoans synthesize and regulate intracellular heme in a cell autonomous manner although genetic evidence in vertebrates suggests that cell non-autonomous mechanisms may exist at the organismal level. In <italic>C. elegans</italic>, a heme auxotroph, extraintestinal tissues are intrinsically dependent on the intestine, which acquires dietary heme for sustenance, supporting the concept that intestinal heme status must be coordinated at the systemic level to regulate whole-organism heme homeostasis. Here we show, by conducting a functional genome-wide RNAi screen in an intestinal-restricted heme sensor worm, that an interorgan heme signaling pathway exists and that >30% of the genes identified from the RNAi screen altered heme homeostasis in the intestine even though these genes are not expressed in the intestine. The biological basis for this signaling is underscored by HRG-7, a cathepsin protease-like protein secreted by the intestine and internalized by distally-located neurons. HRG-7 is specifically secreted from the intestine during heme limitation and <italic>hrg-7</italic> depletion causes embryonic lethality concomitant with a heme deficiency response. Reciprocally, neuron-to-intestine heme signaling is mediated by the bone morphogenic protein homolog DBL-1, which recapitulates hrg-7 deficiency when depleted. Remarkably, depletion of both genes simultaneously results in markedly enhanced growth and heme deficiency phenotypes, suggesting that bidirectional signaling between the intestine and neurons mediates systemic heme homeostasis. Our results have uncovered an unexpected role for a protease family member in long-range communication between organs at the intestinal-neural axis to regulate systemic heme homeostasis in metazoa. As humans have over thirty cathepsin and cathepsin-like proteases, several of which are secreted, we anticipate that these proteins may play analogous roles in mammalian biology.