Introduction:
Intracellular trafficking is a general but tightly regulated process used by various molecules to cross the membranes of living cells. This process is crucial to a large group of bacterial and plant toxins that need to be translocated to the cytosol, where their intracellular targets are located. As most of these toxins use pre-existing transport pathways, the study of these pathways has contributed greatly to identifying and understanding the several novel transport mechanisms present in mammalian cells, including the endocytosis and intracellular distribution pathways. Intracellular trafficking needs to be coordinated with other processes for the cell to function properly. It is clear that intracellular trafficking is important for polarized cell growth and proper signaling. For the development of multicellular organisms, exocytosis and endocytosis are required.
What Is the Role of Intracellular Transport in Neurons?
The neuron is a highly polarized cell and it consists of a single elongated axon and multiple dendrites, which are both extended from its cell body. In order to maintain their proper functioning, neurons rely on intracellular material transport for delivering essential nutrients to the right locations. Studies have shown that the microtubule and the molecular motors are responsible for numerous movements of material in neurons. Microtubules are long and polarized polymers that act as the highway where a variety of materials are shuttled with the help of molecular motors. The polarity of microtubules determines the transport direction of molecular motors. The dysfunction of microtubules has been correlated with certain neurological and neurodegenerative diseases like Alzheimer’s disease, Parkinson’s, and Huntington’s disease.
How Is Transport Step Coordinated?
Individual transport steps are coordinated and occur at two levels-
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First, each transport step between any two compartments involves various vesicular transport steps such as vesicle packaging and formation, its delivery and docking, till its final fusion with the acceptor compartment. Each individual vesicular transport step has to be coordinated.
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The second step involves the integration of individual transport steps from the same pathway, for example, the numerous steps involved in the exocytic and endocytic pathways.
How Is Intracellular Trafficking Coordinated With Other Cellular Processes?
A proper cell function needs proper coordination of all cellular processes, including the intracellular traffic. This section below describes the mechanisms by which intracellular trafficking is coordinated with other cellular processes:
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Intracellular Trafficking and Cell Polarity - In polarized cells, the compartments and functions are distributed asymmetrically. Hence, while establishing the cell polarity, plasma membrane symmetry needs to be broken, and the newly established asymmetry needs to be maintained. In yeast, the cell polarity is crucial for both asymmetric cell division and for response to mating pheromones. In multicellular organisms, cell polarization is required for the polarized tissues to function; for example, asymmetry of the apical and basolateral surfaces is needed for the functioning of epithelial cells, asymmetry of the axonal and dendritic sides is required for the functioning of neuronal cell and asymmetry during stem cell division is required for their differentiation. Consequently, disturbance in the cell polarity can result in cancer and problems in the transmission of information in the brain and also lead to developmental abnormalities. Establishing cell polarity requires coordination in numerous cellular machinery. First, the polarity cues should be positioned on the plasma membrane in response to internal or external signals. Next, the polarity cues need to be decoded, and the actin cytoskeleton and the exocytic pathway need to reorient towards these cues. At last, maintains the cell polarity, which depends on the microtubules.
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Intracellular Trafficking and Signal Transduction - Transduction of external signals through the plasma membrane is important for the cells to interact with their environment. During this process, receptors on the cell surface bind the external ligands, like growth factors, hormones, or neurotransmitters, and transduce the signal inside the cell. This process is important for all cells to function, as well as tissues and organs, and its disruption can result in aberrant cell growth and function, further leading to human disease.
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Intracellular Trafficking and Development - The development of multi-cellular organisms is regulated at the transcriptional level. Although, the regulation of cell-fate transcription depends on the secretion of signals through some cells and also on correct responses to these signals via receiving cells. Hence, proper regulation of both exocytosis and endocytosis is as necessary for development as it is for any other process that is dependent on signaling. In addition to that, the development of some tissues, such as epithelia, neurons, and stem cells, requires polarization that is also dependent on intracellular trafficking.
What Is the Correlation Between Traffic Regulation and Human Disease?
The impairment in the secretion of substances such as hormones, antibodies, and neurotransmitters, defects in the presentation of receptors present on the plasma membrane, and any obstruction in uptaking ligands from the environment can lead to malfunctioning of certain body systems and can cause human diseases. It is also expected that disruption of traffic regulation and coordination can also result in human diseases as well. Because the down-regulation of plasma membrane receptors and quality control of plasma membrane transporters and channels are necessary for the cell response to environmental signals. The regulation of these processes by posttranslational modifications has also been implicated in human disease. For example, dysfunction of the endosomal sorting complex required for transport (ESCRT) machinery, which is needed for targeting ubiquitinated proteins into multi-vesicular bodies, was shown to contribute to cancer and neurodegeneration.
In the past few years, it has been noted that the malfunctioning of trafficking G protein-coupled receptors (GTPases) and their upstream regulators were seen in numerous human disorders. Because the GTPases are expressed ubiquitously, it is considered that they would be involved in numerous common multifactorial disorders. Also, Rabs (GTPases which regulate cell membrane trafficking) , Arfs (GTPases involved in cell proliferation), Rhos (regulate cell motility), and their associated proteins have been seen in endocrinological diseases like diabetes, cancer, immunity disorders, heart disease, and brain disorders like Parkinson's. In addition to that, GTPases and their associated proteins were also seen in some rare monogenic diseases. This implication is most likely due to the differential expression of these regulators in specific tissues at specific times. For example, the ALS2 gene mutation in a Rab5 GEF (guanine exchange factors) has been associated with the neurodegenerative disease amyotrophic lateral sclerosis, mutations in Rab27 result in the rare Griscelli syndrome, Rab8 was implicated in Huntington's disease, and mutations in Rab25 are linked to cancer aggressiveness. Also, infectious viruses, bacteria, and other pathogens can also take over the cell by altering the cellular trafficking regulation for their purposes. Enveloped viruses, such as HIV (human immunodeficiency virus), exploit the ESCRT (endosomal sorting complex required for transport) machinery for their budding, and other intracellular pathogens exploit GTPases and/or their regulators for their reproduction.
Conclusion:
In conclusion, a better understanding of how unobstructed intracellular trafficking flow can be achieved can directly guide the treatment of human diseases that are caused by obstruction of this type of flow. In the future, GTPases and their associated proteins, as well as trafficking-specific post-translational modification machinery, will emerge as new drug interventions are known to target both common and rare human diseases and other pathogen infections.
