Abstract

Introduction: Organelle interplay adds another level of complexity requiring intense analysis to fully understand the cell functioning Inter-organelle signaling plays important roles in cell physiology ranging from cell metabolism, signaling to spatial and temporal adaptation to external and internal perturbations. Nevertheless, how such perturbations orchestrate a coordinated response on specific organelles, and how organelles function influences each other has not been considered or demonstrated in detail. During protein secretion cargo is transported through a series of compartments to reach their destination which are regulated by a Golgi-based control system. Surprisingly we have found that during secretion, Golgi-complex signaling regulate lysosomal dynamics and positioning. Blocking lysosome repositioning revealed an unpredicted and unreported function of lysosomes and autophagy as positive regulators of protein secretion from Golgi-complex. Here we show how coordinated inter-organelle crosstalk results to be crucial to engage functional cellular modules such as microtubule cytoskeleton molecular motors, transport and the nutrient sensing machinery which mutually regulate their function to keep cell homeostasis. Material and Methods: Human cells, cell microinjection, quantitative fluorescence image, shRNA, Results: ER to Golgi transport activates KDELR which in turn increases the number of lysosome-related organelles at the perinuclear area; lysosomal relocation is driven by Dyn-LRB1 phosphorylation at S73 by KDELR-dependent activation of PKA. Inhibition of lysosome relocation and/or autophagy impairs cargo secretion from Golgi to plasma membrane. Discussion: In the framework of the control theory, the KDELR-Golgi-based cascade represent a regulatory circuit to achieve robust functioning in the face of internal drifts and/or exogenous perturbations.In the case of membrane transport, the KDELR actuates as a sensor by the activation of a controller, the Gs-PKA pathway, which mediates the coordinated response involving membrane traffic, actin cytoskeleton microtubules molecular motor protein, lysosome repositioning and autophagy. The KDELR has been implicated in the clearance of neurodegeneration-inducing proteins such as superoxide dismutase 1, a-synuclein, and huntingtin, possibly through modulation of autophagy, and pro-survival properties during the unfolded protein response. Understand how different modulatory systems regulate spatio-temporal organelle coordination to generate cell behavior and keep homeostasis will be helpful to develop pharmacological tools. Those tools will allow us to manipulate such interactions with therapeutic purposes related to neurodegenerative disorders and cancer.