The roles of MYO5B in epithelial cells and the intestine Leng, Changsen
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10.33612/diss.127906021
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Leng, C. (2020). The roles of MYO5B in epithelial cells and the intestine: A focus on microvillus inclusion disease. University of Groningen. https://doi.org/10.33612/diss.127906021
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Chapter 1
Introduction and scope of the thesis
Changsen Leng
Department of Biomedical Sciences of Cells and Systems, section Molecular Cell Biology, University of Groningen, University Medical Center Groningen, Groningen,
Introduction
Myosins
Myosins are best known for the roles in muscle contraction and numerous other motility processes in eukaryotes. Myosins are a large family of cytoskeletal molecular motors that use the energy from ATP hydrolysis to move along actin filaments (1, 2). The structure of myosins comprises of a head, tail and neck domain. The head domain is a conserved catalytic ATP-binding site and moves along actin. The tail domain is highly divergent in various myosin classes and can interact with cargo molecules. The neck is a linker and binds the light chains which have a regulatory function (3). Myosins are found in almost all eukaryotes (4). In humans, the family of myosins includes 40 myosin genes and is classified into 12 classes (5, 6). These classes can be further divided into two groups: one group is conventional myosins which contain the skeletal, cardiac and smooth muscle myosins and the non-muscle myosin II; the other group comprises the unconventional myosins which account for approximately two-thirds of all myosins genes (7). For unconventional myosins, various cellular functions are related to the domains in their tail region, which can combine with different adaptors and other binding proteins (8).
Myosins have been reported in a variety of functions, including not only muscle contraction but also intracellular transport and localization of endosomes and organelles, cell migration and adhesion, signal transduction, cell division and tumor suppression (1). Numerous mutations in myosin genes have been reported to correlate with many different diseases (9-11).
Myosin Vb and MYO5B
The class myosin V is one group of the unconventional myosins. Myosin V forms a dimer and thereby acts as a double-headed motor protein. Myosin V contains more light chains and has a longer “lever arm” when compared to myosin II, which enables it to move in longer steps on the actin (12). Three mammalian isoforms of myosin V motors exist: myosin Va, myosin Vb, and myosin Vc (13). Here, we will focus on the myosin Vb and elaborate its molecular structure and functions.
1
Figure 1. Schematic representation of myosin Vb protein. A. A schematic overview of the
myosin Vb protein and its functional domains. (IQ: Isoleucine-glutamine) B. The diagram shows the myosin Vb structure. Myosin Vb, which is an actin-based molecular motor, can combine with binding protein and transport cargos along the actin filaments.
Myosin Vb (1,848 amino acids, 213,672 Da) is encoded by the MYO5B gene, which is located at chromosome 18 (18q21.1) between 47,349,156 and 47,721,451 bp from the p-arm telomere. MYO5B has a genomic size of 372,296 bases and consists of 42 exons (14). Myosin Vb contains the motor domain, followed by the neck region, and the remaining residues form the tail (Figure 1) which, through direct or indirect interaction with Rab small GTPases proteins, mediate the association with specific membrane-bound organelles (12, 15, 16). Members of the Rab family, including rab8, rab11, rab10, rab25 have been reported to interact with myosin Vb. Thereby, myosin Vb functions to maintain these membrane related proteins at their proper position and regulate recycling endosomal transport (13, 17, 18). Numerous investigations in the last several years have demonstrated that myosin Vb plays an important role in the recycling of internalized membrane proteins to the plasma membrane (Figure 2), and also showed a role of myosin Vb in the establishment of polarized functions in epithelial cells. Loss-of-function mutations in the MYO5B gene can cause disorders of cell polarity and the absence of proteins and microvilli at the enterocyte surface (13, 19, 20).
Figure 2. Schematic representation of endosomal system and the role of myosin Vb protein in
the recycling endosomal trafficking.
MYO5B is ubiquitously expressed in various tissues (21). So far, MYO5B mutations
and/or alterations in MYO5B expression have implicated in several diseases. As most commonly known, loss-of-function mutations in MYO5B can cause microvillus inclusion disease (MVID) (11, 22, 23). Recently, evidence shows the aberrant expression of MYO5B is also closely associated to carcinogenesis and progression of several cancers, including colorectal cancer (CRC), gastric cancer, bladder cancer, acute lymphocytic leukemia (24-29). Besides, recycling endosomes and therewith associated proteins, notably myosin Vb-associated rab11a, have also been implicated in mitotic cell division processes including cytokinesis (30, 31) and orientation of the mitotic spindle apparatus (32–34). In addition, mutations in MYO5B can also cause progressive familial intrahepatic cholestasis (35). However, the mechanism via which mutations/alterations of MYO5B expression lead to these diseases/intracellular dysfunctions is not well understood. In this thesis, we focus on the investigation of the role of MYO5B in intestinal diseases (MVID and CRC) and mitotic spindle orientation in enterocytes, to explore the molecular mechanisms, pathogenesis and therapeutic options.
1
MYO5B and microvillus inclusion disease (MVID)
MVID is a rare congenital diarrheal and malabsorption disorder (36, 37). Among the congenital diarrhea disorders, MVID is one of the most severe diseases, with life-threatening diarrhea developing at an early age (most in the first week of life). No cure exists and patients depend on life-long total parenteral nutrition (TPN) or intestinal transplantation to survive (36, 37). As most patients die during infancy as a consequence of TPN-associated complications, the outcome of MVID patients remains very poor under the current treatment regimens (38).
MVID is caused by mutations in the MYO5B gene in most patients (22, 23, 36, 37, 39– 41) and is characterized by severe (subtotal to total) villus atrophy without signs of inflammation. Characteristic cellular defects include microvillus atrophy, the appearance of pathognomonic microvillus inclusion bodies in the cytoplasm of the villus enterocytes (36, 37), and the mislocalization of brush border proteins involved in
i) dietary nutrient digestion or absorption (e.g., sucrase-isomaltose, dipeptidyl
peptidase IV, glucose/sodium symporter SGLT-1), ii) water resorption (e.g., aquaporins) and iii) electrolyte transport across the brush border membrane (e.g., the sodium/proton exchange protein SLC9A3 (NHE3), the bicarbonate/chloride exchange protein SLC26A3 (DRA) and the chloride and bicarbonate transporter CFTR). Enterocyte defects are more pronounced in the villus than in the crypts (42).
Current treatment of MVID typically requires lifelong TPN to compensate for fecal fluid and salt losses and provide nutrients to support growth. While lifesaving at first, TPN does not stop diarrhea, and most patients die during infancy because of TPN-related complications, that is, sepsis or liver failure (43, 44). Intestinal transplantation is an option but because of its lower 5-year survival rate only for specific cases (45, 46). Clearly, better treatment for patients with MVID is urgently needed.
To demonstrate the causal and mechanistic link between the loss of myosin-Vb and MVID defects, human cell lines as well as mouse and zebrafish models are established in which MYO5B gene expression was abolished. Among the defects in MVID, villus atrophy, which likely contributes most to the reduction in absorptive surface area (47– 49), is also observed in animal models of MVID. The loss of effective absorptive surface area is believed to cause malabsorption and chronic secretory diarrhea.
However, the mechanism responsible for the severe villus atrophy in MVID remains unclear.
The endosomal recycling and degradation pathways are clearly linked (50–52), but the consequence of myosin-Vb depletion for the late endo-lysosomal system is not known. Given the importance of the late endo-lysosomal system for the digestion of maternal proteins in the pre- and neonatal gut and its association with the differentiation of absorptive villus enterocytes, intestinal function and postnatal development (53–56), obtaining insight into these consequences, if any, is imperative.
The role of myosin Vb associated rab11a in the regulation of mitotic spindle orientation
Mitosis is a crucial event that requires major cell reorganization and controls the equal separation of the genetic materials into two daughter cells (57). During this process, the spindle plays a critical role, since its orientation determines the axis of cell division and thereby decides whether the division is symmetry or not. The symmetric mitosis and regulated mitotic spindle orientation play a key role in the development and maintenance of epithelial tissue architecture, which is essential for cell fate decisions, epithelial maintenance, and tissue morphogenesis (58). Mistakes during this process can lead to genetic diseases and relate to the progression of cancers (59–62).
Cell division studies largely focus on the mechanisms that control chromosome behavior and microtubule dynamics (63). Recent studies focused on endosomal trafficking in the process of mitosis, including the regulation of cytokinesis and spindle orientation (64-66). Recycling endosomes together with the associated proteins, notably the myosin Vb binding protein rab11a, have also been implicated in mitotic cell division processes. Thus, rab11a-associated recycling endosomes are required for elongation of the cytokinetic furrow and contribute to mitotic spindle organization and orientation (30–34, 67, 68). Notably, as myosin Vb is a recycling endosome-associated protein that interacts with rab11a and is implicated in cell polarity, cancer and tissue architecture defects, it is conceivable that myosin Vb contributes to mitotic cell division, but this has not been experimentally addressed.
1
The role of MYO5B in carcinogenesis and potential ability to regulate chemosensitization of colorectal cancer (CRC)
MYO5B plays an important role in endosome recycling and endo-lysosome
homeostasis in the intestinal epithelial cells (13, 69). Regulated endosomal trafficking is crucial for epithelial cell polarity and intestinal tissue architecture development (70). Evidence shows that mammalian epithelial cancer cells lose polarity when they progress to malignancy (71). During cancer progression, the expression of proteins at the intestinal brush border is reduced, which is related to the loss of cell polarity and epithelial architecture (72). Besides, loss of polarity is linked to carcinogenesis. Not only it may lead to asymmetric cell division, but also destroy the maintenance of the apical junctional complex (73). It has been reported that an aberrant expression of
MYO5B is closely associated with the carcinogenesis and progression of several
cancers, including gastric cancer, bladder cancer, acute lymphocytic leukemia (25-29). For instance, inactivation of MYO5B promotes motility and invasion in gastric cancer cells (25, 27).
In addition, recent evidence shows MYO5B expression is correlated to CRC tumorigenesis and prognosis. CRC patients with low MYO5B expression displayed shorter overall and metastasis-free survival and MYO5B acted as a strong prognostic factor for CRC recurrence (24). Overexpression of myosin Vb binding protein rab11-FIP2 in colorectal cancer cells promotes tumor migration and angiogenesis (74). CRC is the third most frequently diagnosed cancer and the fourth most common cause of cancer-related deaths in the world (75). Identifying individual-based and effective treatment strategies is urgent for the patients with this malignant tumor.
Chemotherapy is important for the treatment of CRC (76, 77). Platinum antitumor drugs mainly include cisplatin (DDP), carboplatin (CBDCA) and oxaliplatin (LOHP). Platinum-based chemotherapy is widely employed for the treatment of a wide array of solid malignancies, including colorectal cancer (77, 78). However, treatment with platinum drugs often results in the development of chemoresistance via several different mechanisms (79). Hence, the development of chemosensitization strategies and predictors for chemotherapy will have important clinical implications. Notably, copper transporters such as ATP7A and ATP7B, have been demonstrated to control the cellular efflux of platinum (80), and previous studies implicated myosin Vb in the
delivery of ATP7B in hepatocytes (81). Further, the endo-lysosome system through sequestering and transporting antitumor drugs can also regulate chemosensitivity of cells (82-84). Plausibly, MYO5B may also be involved in the regulation of sensitivity to platinum drugs in cancer cells. However, this has not been experimentally addressed.
1
Scope of the thesis
Chapter 1 Introduction and scope of the thesis.
Chapter 2 In this chapter, we reviewed all published MVID case reports in order to retrieve pharmacological interventions that have been tried for individual patients as part of their clinical care.
Chapter 3 By using cell model and human tissue, we have investigated the consequences of myosin Vb depletion on the late endo-lysosomal system, the underlying mechanisms, and the possible implications for the pathogenesis and treatment of MVID.
Chapter 4 We have investigated the alterations of the late endo-lysosomal system in
MYO5B knockout mouse enterocytes and investigated the potential of the antioxidant
N-acetylcysteine (NAC) as a pharmacological treatment for MVID.
Chapter 5 We have investigated mitotic cell division following the loss of MYO5B expression in intestinal epithelial cells and try to find correlations between loss of
MYO5B and the aberrant cytokinesis and mitotic spindle orientation.
Chapter 6 We have studied the effects of loss of MYO5B on cisplatin sensitivity of human intestinal epithelial Caco2 cells. We attempted to explore the mechanism by which way myosin Vb influences the sensitivity of colorectal cancer cells to cisplatin. Chapter 7 Summary and perspectives.
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