User:Salient.Masonry/SUMO protein/Bibliography

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Bibliography

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• Bedford, L., Lowe, J., Dick, L. et al. Ubiquitin-like protein conjugation and the ubiquitin–proteasome system as drug targets. Nat Rev Drug Discov 10, 29–46 (2011). https://doi.org/10.1038/nrd3321
  • This article mentions two other ubiquitin-like modifiers beyond SUMO: NEDD8, and ISG15. They have similar protein dynamics but distinct pathways, with some overlap or cross-talk as well.
• Cheng X, Yang W, Lin W, Mei F. Paradoxes of Cellular SUMOylation Regulation: A Role of Biomolecular Condensates? Pharmacol Rev. 2023 Sep;75(5):979-1006. doi: 10.1124/pharmrev.122.000784. Epub 2023 May 3. PMID: 37137717; PMCID: PMC10441629.
  • This paper reiterates the role of sumoylation in cancer, cardiovascular disease, neurodegeneration, infection, and possibly others, reinforcing its significance in both science and human health.
• Ivan Psakhye, Federica Castellucci, Dana Branzei. SUMO-Chain-Regulated Proteasomal Degradation Timing Exemplified in DNA Replication Initiation. Molecular Cell. Volume 76, Issue 4, 2019, Pages 632-645.e6, ISSN 1097-2765, https://doi.org/10.1016/j.molcel.2019.08.003.
  • Discussion of yeast studies with SUMO, mentioning mechanistic aspects such as SUMO-targeted ubiquitin ligase or StUbL being Slx5/8, SUMO protease Ulp2 which prevents the action of a StUbL, Cdc48 segregase which dissociates a protein from a bound protein which has been SUMOylated and subsequently ubiquitinated by StUbL to be destroyed by proteasome later.
• Chang S.C., Ding J.L. Ubiquitination and SUMOylation in the chronic inflammatory tumor microenvironment. (2018) Biochimica et Biophysica Acta - Reviews on Cancer, 1870 (2) , pp. 165-175.
  • Starts to explain the role of SUMO in certain cancers which have an inflammatory phenotype.
• Andrew Vargas Palacios, Pujan Acharya, Anthony Stephen Peidl, Moriah Rene Beck, Eduardo Blanco, Avdesh Mishra, Tasneem Bawa-Khalfe, Subash Chandra Pakhrin, SumoPred-PLM: human SUMOylation and SUMO2/3 sites Prediction using Pre-trained Protein Language Model, NAR Genomics and Bioinformatics, Volume 6, Issue 1, March 2024, lqae011, https://doi.org/10.1093/nargab/lqae011
  • Discusses human protein candidates for regulatory binding of SUMO, the paralogs SUMO1, SUMO2, and SUMO3, and the technology being used to predict interactions.
• Leaving off here.

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In human proteins, there are over 53,000 SUMO binding sites, making it a substantial component of fundamental biology.

SumoPred-PLM or SUMOylation site Prediction using Protein Language Model - An AI deep learning utility to predict based on known biological rules around SUMO2 and SUMO3 binding in human proteins incorporating knowledge from a separate pretrained PLM tool developed previously in 2021 by Elnaggar et al. known as ProtT5-XL-UniRef50. Collaboration between multidisciplinary AI tools is becoming common practice.

DeSUMOylation

In yeast, SMT3 encodes the SUMO protein, and SUMO E3 ligase attaches SUMO to target proteins. In cell cycle regulation, the base case is that SUMO ligation is constantly taking place, leading to polySUMOylation of eligible target proteins. This is countered by the SUMO protease ULP2 which cleaves polySUMO groups, leaving the protein in a monoSUMOylated state. As shown in the Biorender figure, there is a feedback mechanism in which ULP2 maintains the monoSUMOylated state by passively and diligently cleaving SUMO such that the polySUMOyated state is never stabilized enough to be acted upon by downstream actors. This deSUMOylation is critical to prevent precocious advancement of the cell cycle as discussed in several studies.

The deSUMOylation may be arrested by the inhibitory phosphorylation of the ULP2 SUMO protease by the kinase Cdc5. By inhibiting the deSUMOylation of Ulp2, polySUMOylation is then promoted as the new stable state of target proteins, which are often but not always bound to other proteins in order to regulate major changes within the cell. Cdc5 is countered by the Rts1-PP2A phosphatase, which maintains the active state of the Ulp2 SUMO protease by removing the phosphate group added by Cdc5 kinase.

The consequence of disrupting the counteracting deSUMOylation is the following: First, the targeted protein becomes polySUMOylated. Second, SUMO Targeted Ubiquitin Ligase, or STUbL, (SLX5 or SLX8 in the case of yeast) may then bind the polySUMOylated target and attach Ubiquitin groups (often polyUbiquitinating the already polySUMOylated protein). Third, Segregases such as Cdc48 may then dissociate the SUMOylated and ubiquitinated target from its bound protein. Fourth, the dissociated protein may then be degraded by the canonical Ubiquitin-proteasome pathway while the unbound protein it had been bound to is now free to do what it could not do while bound.

As studied with budding yeast, in the case of Tof2-Cdc14, Cdc14 release from the nucleolus allows the Mitotic Exit Network to commence, but it is regulated by the binding of Tof2, a protein subject to SUMOylation. Likewise, the Cohesin protein which binds sister chromatids in metaphase is able to be targeted by SUMOylation to allow the Cdc48 segregase to separate Cohesin and allow sister chromatid separation in early anaphase.

In research as is often the case, scientists test drugs known to have significant effects on living systems; one such example is Rapamycin, the well-known inhibitor of mechanistic Target of Rapamycin, or mTOR. With respect to SUMOylation, Rapamycin may be thought of as having a "Sledge Hammer" effect, in which the drug promotes cellular autophagy, part of which includes broad-spectrum promotion of nonspecific SUMOylation. This may be beneficial in some circumstances as it supports the breakdown of accumulated waste products.

In the case of the human p53 tumor suppressor protein, it too is subject to SUMOylation and removal from the nucleus in a pathway distinct from the MDM2 pathway which functions to achieve a similar end.

In Human Pathology (New Section)

SUMO protein is implicated in the etiology of many biomedical disease states not limited to: cancer, atherosclerosis, diabetes, neurodegenerative diseases, cardiovascular diseases, liver diseases, intestinal disorders, and infectious diseases.

In the case of the well-studied cancer tumor suppressor known as p53, there is a regulatory ubiquitin ligase protein in humans called Mouse Double Minute 2 protein, or MDM2, which acts to remove p53 from the cell. MDM2 regulates itself through self-ubiquitination by way of a RING finger domain, targeting itself for proteasomal destruction. When it is SUMOylated at the RING finger domain, MDM2 no longer limits its own function in the cell. When protected from itself, it likewise ubiquitinates p53, marking the protective p53 for destruction instead, whose absence is understood to promote cancer. Here again, the base case is SUMOylation, which is actively being undone by newly discovered SUMO protease SUSP4 and also by the SUMO protease interaction of SMT3IP1/SENP3 which is understood to deSUMOylate both MDM2 and p53. One of the ways p53 functions is as a DNA-binding tetramer; interestingly, SUMOylation of p53 delocalizes it from the nucleus, which prevents such activity. The critical nature of p53 cannot be overstated: in fact, if a human carries only one non-functioning copy of p53, it results in a deadly cancer prognosis known as Li Fraumeni syndrome. Beyond p53, in cancer, many oncogenes and tumor suppressors have been discovered to be SUMOylated in order for the cancer to progress or not, with each SUMOylation event having one of a variety of effects. When IκB is SUMOylated, the SUMO post-translational modification outcompetes ubiquitination, protecting it from degradation, and by extension, the transcription factor NF-κB is bound in a complex with IκB, preventing the expression of genes that may otherwise cause cells with DNA damage to apoptose. In hypoxic conditions as arise in some cancers, HIF-1α, which is usually SUMOylated followed by subsequent ubiquitination and degradation through the von Hippel-Lindau tumor suppressor's ubiquitin ligase activity, is instead deSUMOylated thereby promoting survival of the tumorigenic cells. The fallout from deSUMOylating HIF-1α includes promotion of MMPs which are understood to contribute to the progression of EMT, a hallmark of cancer.

In atherosclerosis, both p53 and ERK5 are SUMOylated by the stimulus of disturbed blood flow. The stimulus is transduced by the activation of a serine/threonine kinsase called p90RSK, which phosphorylates the human SUMO protease SENP2 at the throenine amino acid residue 368. That phosphorylation is sufficient for the delocalization of the SENP2 from the nucleus. The effects of this phosphorylation-dependent SENP2 inhibition by nuclear export include the SUMOylation of p53 which leads to endothelial cell apoptosis, and SUMOylation of ERK5 which leads to inflammation. Nuclear export of SENP2 additionally downregulates endothelial nitric oxide synthase, eNOS while it upregulates inflammatory adhesion molecules. As eNOS is required for healthy vascular physiology, pathological oxidative stress ensues in vascular endothelial cells. With the oxidative stress comes subsequent accumulation of cellular lipids; this results in the inflammatory foamy cell state that is typified by atherosclerosis as well as the similarly inflammatory myelin-laden macrophages known to produce chronic inflammation in SCI.

In cardiovascular disease, many proteins are subject to SUMOylation. To say SUMOylation itself is bad or good regarding this or any class of disease is to overlook the role of the multiple proteins in question. One common denominator among many conditions is fibrosis; in myocardial fibrosis, PPARγ1 is understood to have a role in regulating expression of some key genes, and its transcriptional activity is generally inhibited by SUMOylation. Therefore, one possible therapeutic intervention in the case of cardiac hypertrophy is countering the SUMOylation of PPARγ1.

In neurodegenerative disease, we often observe pathological accumulation of proteins. Inclusion bodies form when for example, the Huntington's disease protein, aptly named Huntingtin, accumulates and folds into a form which is impervious to the proteasome. In Huntington's disease, sufficient SUMOylation of the anomalous Huntingtin protein prior to such refolding could perhaps delay the progression of the disease state by enabling timely destruction of the protein while the polypeptide chains are still accessible to the protease subunits within the proteasome. Other accumulating proteins which threaten neurodegenerative disorders include α-synuclein (associated with Parkinson's) and Amyloid β (associated with Alzheimer's), and if acted upon early enough could perhaps be better mitigated.

In liver disease, the healthy state includes...

Human Papillomavirus is understood to upregulate the SUMO ligase UBC9 to such an extent that it is suggested as a means of screening for the oncogenic virus. . HPV encodes an oncoprotein known as E6, which promotes binding of...