Stimulation of cell invasion by the Golgi Ion Channel GAAP/TMBIM4 via an H2O2-Dependent Mechanism

Nuno Almeida,Guia Carrara,Carlos M Palmeira,Ana S Fernandes,Maddy Parsons,Geoffrey L Smith,Nuno Saraiva

doi:10.1016/j.redox.2019.101361

Nuno Almeida, Guia Carrara + Show 5 more

Open Access

https://doi.org/10.1016/j.redox.2019.101361

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Abstract

The mechanisms by which the Golgi apparatus (GA) impacts on cell invasion are poorly understood. The human Golgi Anti-Apoptotic Protein (hGAAP, also known as TMBIM4) is a highly conserved Golgi cation channel that modulates intracellular Ca2+ fluxes. Human GAAP is expressed in all human tissues, is essential for cell viability and provides resistance against a range of apoptotic stresses. Furthermore, hGAAP enhances adhesion and cell migration by increasing the turnover of focal adhesions due to activation of store-operated Ca2+ entry.Here, we describe a GA-derived mechanism that controls cell invasion. The overexpression of hGAAP stimulates 3-dimensional proteolytic cell invasion by a mechanism that is dependent on the accumulation of intracellular hydrogen peroxide, which might be produced by the hGAAP-dependent stimulation of mitochondrial respiration.These findings provide new insight into the complex mechanisms by which Ca2+ and reactive oxygen species signaling contribute to cell invasion and to the role of the GA in these processes.

Highlights

Cell motility, and cell invasion, plays an important role in physiological phenomena such as immune cell infiltration and embryogenesis, and in pathological processes like tumor growth and metastasis
The results showed a significant increase in directed migration through uncoated and 3D Matrigel coated chambers in cells overexpressing human Golgi Anti-Apoptotic Protein (hGAAP), but not those expressing hGAAP Ctmut (Fig. 1B–D)
The use of the Ctmut hGAAP served to discard the possibility of protein overexpression-induced UPR activation, changes in membrane or protein trafficking or other more subtle mechanisms to account for the observed effects

Summary

Introduction

Cell invasion, plays an important role in physiological phenomena such as immune cell infiltration and embryogenesis, and in pathological processes like tumor growth and metastasis. Cell invasion involves intricate coordination of adhesion and cytoskeletal remodeling that can be influenced by various cellular processes including metabolism, intracellular and extracellular pH, reactive oxygen species (ROS) accumulation, Ca2+ fluxes and membrane trafficking [1,5,6,7,8,9,10]. The complexity of these regulatory mechanisms is increased by the interplay between several of the abovementioned elements. Ca2+ signaling can regulate key cellular events that are fundamental to an invading cell, such as mitochondrial metabolism, cytoskeleton remodeling, focal adhesion (FA)

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