Mitochondrial E3 Ubiquitin Ligases in Cancer Therapy: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Jacopo Di Gregorio.

Ubiquitination is a post-translational modification that targets specific proteins on their lysine residues. Depending on the type of ubiquitination, this modification ultimately regulates the stability or degradation of the targeted proteins. Ubiquitination is mediated by three different classes of enzymes: the E1 ubiquitin-activating enzymes, the E2 ubiquitin-conjugating enzymes and, most importantly, the E3 ubiquitin ligases. E3 ligases are responsible for the final step of the ubiquitin cascade, interacting directly with the target proteins. E3 ligases can also be involved in DNA repair, cell cycle regulation and response to stress; alteration in their levels can be involved in oncogenic transformation and cancer progression. Of all the six hundred E3 ligases of the human genome, only three of them are specific to the mitochondrion: MARCH5, RNF185 and MUL1. 

  • ubiquitin ligase
  • cancer
  • mitochondria

1. Introduction

Among the post-translational modifications, ubiquitination is one of the most extensively studied. Ubiquitination consists of the attachment of ubiquitin, a small protein of 76 amino acids in length, on specific lysine (K) residues of the targeted protein [1]. The attached ubiquitin can undergo further ubiquitination, and depending on the specific lysine residue on the ubiquitin sequence (K6, K11, K27, K29, K33, K48 and K63), different poly-ubiquitin chains can be formed and are named after the specific lysine residue [2].
The different ubiquitination types lead to different cell fates: among the most important, K48 ubiquitination brings the tagged protein to the proteasome for degradation, K63 ubiquitination is related to various cellular processes such as endocytic trafficking, inflammation and DNA repair, K11 is implicated in mitotic regulation and endoplasmic-reticulum-associated degradation (ERAD), K6 is involved in DNA repairs and DNA modifications such as methylation, and K27 is involved in mitochondrial DNA repair [3].
The process of ubiquitination is a multi-reaction cascade and requires three different classes of enzymes, each one catalyzing a different step of the reaction. The enzymes are classified into E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzymes) and E3 (ubiquitin ligases). The E1 activating enzyme activates ubiquitin at its C-terminus in an ATP-dependent manner: this enables ubiquitin to be transferred by the E2 conjugating enzymes to the E3 ligases that are capable of binding both the E2 and the specific substrate [4,5][4][5].
The third step, the most important of the cascade, is called “ligation” and is mediated by an E3 ubiquitin ligase that transfers ubiquitin from the E2 to the specific substrate. E3 ligases mediate the specificity of the ubiquitination reaction by recognizing specific structures and motifs on the targeted protein. Outside of the catalytic core, the rest of the structure of the E3 ligases is responsible for recognizing the specific substrate. Paired with the specific localization of those enzymes, which allows ubiquitination of the co-localized substrates, this creates a vast network of post-translational regulation, resulting in protein quality control, degradation of overproduced proteins and their activation and localization [5].
To allow ubiquitination and control of so many different substrates, in the human genome, there are more than a thousand different E3 enzymes, divided into four classes based on the structure of their catalytic domain: HECT (homologous to the E6AP carboxyl terminus), RING (Really Interesting New Gene), U-Box and RBR (RING-IBR-RING, a hybrid between HECT and RING). The four classes of E3 enzymes are responsible for different cellular functions [5].
Each E3 ligase can recognize and interact with several substrates. Depending on their substrates, as well as the different lysine residues that are ubiquitinated, E3 ligases can then be involved in a plethora of cellular and physiological processes. Moreover, alteration in the function of the E3 ligases can lead to several pathological scenarios [6]. In fact, the loss of activity of an E3 ligase would result in the accumulation of its targets, which may lead to pathology. On the other hand, excessive activity of one or more E3 ligases would mean complete degradation of their targets and ultimately their loss of function [6].
Alterations and mutations of a wide number of E3 ligases have been linked to different neurological diseases, such as encephalopathy, ataxia or Parkinson’s disease [7,8][7][8].
Furthermore, dysregulation of E3 ligases, both in the form of hyperactivation and downregulation, has been associated with cancer progression, as well as with evasion from cell death, and metastasis [9].
Another common trait in many tumors is the alteration of mitochondria: this leads not only to metabolic changes in the neoplastic cells but also to an alteration in the production of reactive oxygen species, as well as in their signaling, increased proliferation and changes in the interactions with the tumor microenvironment [10].
When merging these two concepts, it becomes clear that understanding the alterations in the mitochondrial E3 ubiquitin ligases may be relevant for finding new strategies for cancer therapy. There are only three E3 ligases specifically localized in the mitochondria: MARCH5, RNF185 and MUL1, also called collectively “mito E3 ligases”. These enzymes are all RING finger-type ligases and are capable of ubiquitinating also cytosolic targets.

2. Membrane-ARCH5ssociated RING-CH Protein V Protein 

The Membrane-Associated RING-CH Protein V protein (MARCH5) is located in the outer mitochondrial membrane (OMM). Also known as MITOL and RNF153, it was first identified in 2006 and associated with mitochondrial dynamics: in fact, MARCH5 targets for K-48 ubiquitination the mitochondrial proteins Mitofusin 2 (MFN2) and Dynamin Related Protein 1 (DRP1), thus contributing to the regulation of mitochondrial fission and fusion [11]. Other well-established targets of MARCH5 include the DRP1 receptor MiD49 [11], the mitochondrial quality control protein FUN14-Domain-Containing Protein 1 (FUNDC1) [12], the retinoic acid-inducible gene-I (RIG-I) receptor [13], the ER-associated endoribonuclease IRE1α [14] and the mitochondrial antiviral signaling (MAVS) protein [15]. MARCH5 has thus been canonically involved in mitochondrial protein quality control, mitophagy, ER stress and unfolded protein response (UPR), innate immune response and prevention of cell senescence. Via ubiquitination of MFN2, MARCH5 mediates the physical interaction between mitochondria and the ER, allowing the exchange of lipids and calcium ions at the membrane contact site. Depletion of MARCH5 has been related to the disruption of the membrane contact site and the aggravation of derangements caused by progressive diseases [16]. Due to its role in mitochondrial quality control, MARCH5 has been associated with neurodegenerative diseases, where damaged proteins may translocate to the mitochondria. Consequently, this connects MARCH5 also to senescence and aging. This suggests the use of MARCH5 activators, such as berberine, as anti-aging drugs [17].
MARCH5 is regulated by auto-ubiquitination [16], targeting itself for proteasomal degradation to maintain correct mitochondrial homeostasis. In addition, it can be negatively regulated by the mir-30a microRNA [17].
In the context of cancer, MARCH5 tends to act as an oncogene, with different mechanisms that depend on the cellular context and are characterized by the specific targets of the ligase.
In fact, MARCH5 can be found upregulated in breast cancer (BC): high levels of the ligase have been found in several BC cell lines, as well as in cultures derived from BC patients [18], mainly due to a downregulation of mir-30a. MARCH5 expression in the context of BC is related to poor prognosis [19]. Increased MARCH5 expression results in lower levels of its targets such as DRP1 and MFN2 and altered autophagy, ultimately leading to dysfunctional mitochondria, increased reactive oxygen species (ROS) production and increased aggressiveness and metastatic potential. This was proven by knocking down MARCH5 in a model of BC cells that led to reduced cell growth and metastatic ability. This was also shown in vivo in an MDB-MB xenograft on MARCH5 KO mice where it caused slower tumor growth and a smaller number of metastases [19].

3. RINFG Finger Protein 185

RING Finger Protein 185 (RNF185) is located in the outer mitochondrial membrane, with its RING domain facing the cytosol. It was first identified in 2013, and it was first associated with ERAD, the process by which the unfolded proteins that accumulate in the ER are transported to the cytosol for degradation by the proteasome [38][20]. Directly or indirectly, RNF185 regulates several cell processes such as autophagy, immune response and endoplasmic reticulum protein degradation [38,39,40][20][21][22]. RNF185 regulates autophagy by stimulating LC3II accumulation and autophagosome formation in human cells. More specifically, RNF185 regulates selective mitochondrial autophagy, thus modulating mitochondrial homeostasis [40][22]. RNF185 regulates innate immune response by binding and regulating, through ubiquitination, the cyclic GMP-AMP synthase (cGAS) which is involved in the activation of the stimulator of interferon genes (STING) and innate immune response [39][21]. RNF185 deregulation is involved in several diseases. As shown by the reviewed studies below, RNF185 has been shown to act as a tumor suppressor, and thus, its lack of function is reflected in the development of cancer. RNF185 is downregulated by the long non-coding RNA (lncRNA) RNF185-AS1. This has been found significantly upregulated in the hepatocellular carcinoma (HCC) serum of HCC patients, and high levels of RNF185-AS1 were found in HCC cells. It promotes HCC cell proliferation, epithelial–mesenchymal transition (EMT), migration and invasion while RNF185-AS1 knock-down inhibits the same processes. The invasive phenotype has been found to be mediated by the mR-221-5p/integrin β5 axis, and thus, its targeting may hold the promise for a possible therapeutic strategy in HCC [41,42,43][23][24][25]. RNF185-AS1 has also been found highly overexpressed in papillary thyroid carcinoma (PTC). This high expression has been found associated with larger tumor size, lymph node metastasis and advanced cancer stage in PTC patients. The mechanism of action is mediated by the downstream miR-429/lipoprotein-receptor-related protein (LRP4) axis. RNF185-AS1 silencing has been found capable of impeding the proliferation, migration and invasion of the cancer cells in vitro and to reduce tumorigenesis in vivo. Thus, the RNF185-AS1/miR-429/LRP4 axis may represent a potential target for the development of therapeutic strategies in PTC [44][26]. Downregulation of RNF185 expression has been found to correlate with prostate cancer progression and metastasis, and when RNF185 is reduced, the wound healing and cellular movement pathways were the most significant that were found upregulated. The deregulations were implicated with EMT and the acquisition of the migration phenotype. Collagen type III alpha 1 chain (COL3A1) has been identified as the main mediator of RNF185’s ability to promote the migration phenotype in prostate cancer cells as COL3A1 inhibition was capable of attenuating the migration and metastasis of the cancer cells [45][27]. Thus, the replenishment of RNF185 or the targeting of COL3A1 may be considered as possible strategies for prostate cancer therapy.

4. Mitochondrial ULbiquitin Ligase 1 

Mitochondrial Ubiquitin Ligase 1 (MUL1) is also a RING E3 ligase. It is located in the outer mitochondrial membrane (OMM), with its active RING domain facing the cytoplasm. This makes this mitochondrial E3 ligase capable of ubiquitinating cytosolic targets. It was first identified in 2008, and it is also known as MULAN (Mitochondrial Ubiquitin Ligase Activator of NFkB), MAPL (Mitochondrial Anchored Protein Ligase), GIDE (Growth-Inhibition and Death E3 Ligase) and HADES [60,61][28][29]. Other than its E3 ubiquitin ligase activity, MUL1 can also function as a SUMO E3 ligase, targeting different targets for SUMOylation [62][30]. This further broadens MUL1’s range of activities and molecular processes in which the ligase is involved, depending on the various targets of the ligase and the type of post-translational modification involved. Known substrates of MUL1 include DRP1, MFN2, ULK1, Akt2, STING and p53. In addition, MUL1 has been linked to different cellular processes, such as mitochondrial dynamics, apoptosis, mitophagy, innate immune response and mitochondrial and cellular metabolism. MUL1 is mostly known for its involvement in mitophagy, where it can act independently of Parkin in order to regulate the process [63,64,65,66,67,68,69,70,71,72,73,74][31][32][33][34][35][36][37][38][39][40][41][42]. MUL1 can also regulate the mitophagy mediated by Parkin, by SUMOylating and activating the autophagic receptor NDP52, a well-known Parkin activator [75][43]. MUL1 can be regulated at the mitochondrial level by the action of the serine protease Omi/HTRA2, thus keeping its levels at a steady state [71][39]. MUL1 expression can also be regulated by AMPK activity [76][44]. In addition, MUL1 can regulate itself via auto-ubiquitination [77][45]. Overall, MUL1 dysregulations can impact several pathologies, such as inflammatory, cardiovascular and neurological diseases; MUL1 has been proposed as a potential therapeutic target, concerning especially the mitochondrial derangements that may occur during these diseases [78][46]. In the context of cancer, MUL1 can act both as an oncogene and as a tumor suppressor. The reason for this dualistic effect ultimately relies on the different targets of MUL1, which if dysregulated can lead to the activation of pro- or anti-tumoral pathways.

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