Cytoplasmic vacuolization in cell death and survival

Abstract

Cytoplasmic vacuolization (also called cytoplasmic vacuolation) is a well-known morphological phenomenon observed in mammalian cells after exposure to bacterial or viral pathogens as well as to various natural and artificial low-molecular-weight compounds. Vacuolization often accompanies cell death; however, its role in cell death processes remains unclear. This can be attributed to studying vacuolization at the level of morphology for many years. At the same time, new data on the molecular mechanisms of the vacuole formation and structure have become available. In addition, numerous examples of the association between vacuolization and previously unknown cell death types have been reported. Here, we review these data to make a deeper insight into the role of cytoplasmic vacuolization in cell death and survival.

Keywords: microbial toxins; regulated cell death; vacuolization; viruses.

Figure 1. Mechanisms of vacuolization triggered by methuosis inducers

A. Stages of vacuole formation induced by Ras oncogenes. 1, H-RasG12V and (presumably) K-RasBG12V activate GTPase Rac1; 2, activated Rac1 stimulates macropinocytosis; 3, active Rac1 associates with GIT1 to inactivate Arf6, which blocks the recycling of macropinosomes to the plasma membrane; 4, accumulated macropinosomes acquire some properties of late endosomes and fuse to form vacuoles. B. Vacuole formation triggered by other methuosis inducers. CK1, casein kinase 1; MKK4, mitogen-activated protein kinase kinase 4; Nuc, nucleolin; GIT1, G protein-coupled receptor kinase interacting ArfGAP 1; Arf6, ADP-ribosylation factor 6; EEA1, early endosome antigen 1; NGF, nerve growth factor. The figure was produced using Servier Medical Art (http://www.servier.com).

Figure 2. Mechanisms of action of inducers of paraptosis and paraptosis-like cell death

The names of the inducers of paraptosis and paraptosis-like cell death (PLCD) are given in colored frames; their pathways are marked by arrows of the corresponding color. Stages of PLCD induced by activation of big conductance calcium-activated potassium channels (BKCa) by reactive oxygen species (ROS) are indicated by numbers: 1, ROS enter the cytoplasm; 2, ROS activates heme-oxygenase 2 (HO-2) and NADPH-P450 reductase (NPR); 3, carbon monoxide (CO) is produced by HO-2 and NPR; 4, BKCa activation by CO leads to K⁺ release from the ER and mitochondria to the cytoplasm and from the cytoplasm to the extracellular space; 5, low intracellular K⁺ concentration is compensated by the entry of Na⁺ accompanied by water into the cell; 6, low K⁺ concentration in the ER and mitochondria is compensated by the entry of Na⁺ and water, which leads to mitochondrial swelling and ER vacuolization; 7, intracellular Na⁺ concentration decreases through the activation of Na⁺/H⁺-antiporters and Na⁺/K⁺ ATPase. Under conditions of mitochondrial dysfunction induced by ROS and BKCa opening, the activity of ATP-dependent Na⁺ transporters depletes the ATP pool and causes cell death. OpA, ophiobolin A; IP₃R, inositol trisphosphate receptor; ERAD, endoplasmic reticulum-associated protein degradation; Hsp90, heat shock protein 90; VCP/p97, valosin-containing protein; mPTP, mitochondrial permeability transition pore; and MCU, mitochondrial calcium uniporter. The figure was produced using Servier Medical Art (http://www.servier.com).