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After "deep-diving" into autophagy and impaired autophagy, one of the twelve hallmarks of aging, it makes sense to shine some light on its equally important (however not so famous) partner in cellular housekeeping: the proteasome. It ́s primary function is breaking down proteins that are no longer needed, damaged, or misfolded [1]. Similar to autophagy, it is our body's and skin's very own trash and recycling system, working 24/7 to keep our cells healthy and functioning [2]. The human body is composed of approximately 16-20% protein by weight. This percentage can vary based on factors like age, sex, and overall body composition. Skin, is particularly rich in proteins, about 25-30% of the total protein in the human body is found in the skin and the dry weight of skin is approximately 70% protein. Loss of proteostasis (balance of protein synthesis, folding, and degradation) is one of the twelve hallmarks of aging and the proteasome is an important mechanism within the proteostasis network [3].
THE PROTEASOME The proteasome is a large, barrel-shaped protein complex found in all eukaryotic cells, responsible for the degradation of intracellular proteins [4]. It plays a crucial role in maintaining cellular homeostasis by selectively breaking down short-lived, damaged, or misfolded proteins [5]. The 26S proteasome consists of a 20S core particle and one or two 19S regulatory particles [6]. Proteins targeted for degradation are typically tagged with ubiquitin molecules, which are recognized by the 19S regulatory particle, allowing the protein to be unfolded and fed into the 20S core for proteolysis [7]. The ubiquitination process provides a highly selective mechanism for targeting proteins for degradation in comparison to other systems like lysosomes. Proteasomal degradation is an ATP-dependent process:
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This process is crucial for:
▌Maintaining protein quality control [12] ▌Regulating cellular processes by controlling protein levels ▌Recycling amino acids for new protein synthesis The proteasome is involved in numerous vital cellular processes (see illustration), including: ▌Cell cycle regulation ▌Transcriptional control ▌Immune responses ▌Neuronal plasticity Its proper function is essential for cellular health, and dysfunction of the proteasome system has been implicated in various diseases, including neurodegenerative disorders and cancer. The proteostasis network The proteostasis network (PN) is a complex system of cellular machinery that maintains the integrity of the proteome consisting of collaborating systems to ensure proper protein folding, repair damaged proteins and eliminate those beyond repair. ▌Molecular chaperones and co-chaperones ▌The ubiquitin-proteasome system (UPS) ▌Autophagy machinery ▌Translational machinery ![]()
PROTEASOME VS AUTOPHAGY
Complementary cleaning and recycling systems While the proteasome primarily handles short-lived and soluble proteins, autophagy is responsible for degrading long-lived proteins, protein aggregates, and even entire organelles [13]. The proteasome plays critical roles in cell cycle control, gene expression, protein quality control, and immune responses, while other systems like autophagy are more involved in bulk degradation and cellular remodeling. The systems are not entirely independent and often work together to maintain cellular health [14]. The ubiquitin-proteasome system (UPS) and autophagy interact through various mechanisms:
PROTEASOME AND EPIGENETICS The proteasome also plays a significant role in epigenetics - the study of heritable changes in gene expression that don't involve changes to the underlying DNA sequence and recognised as one of the hallmarks of aging [19]. The proteasome influences epigenetics through several mechanisms: ▌Histone regulation + modification: The proteasome degrades histones, proteins that package DNA, influencing chromatin structure and gene accessibility [20].. ▌Transcription factor control + regulation: By regulating the levels of transcription factors, the proteasome indirectly affects gene expression patterns [21]. ▌Epigenetic modifier turnover + DNA methylation: The proteasome controls the levels of enzymes that modify histones and DNA, such as histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) [22]. ▌Non-proteolytic functions: Some proteasome subunits have been found to directly interact with chromatin, suggesting a more direct role in gene regulation [23]. These interactions create a complex feedback loop between protein degradation and gene expression, highlighting the proteasome's far-reaching influence on cellular function PROTEASOME AND (SKIN) HEALTH The proteasome is likely present in skin cells and in extracellular fluids associated with skin, such as sweat and plays a vital role in maintaining health and skin quality by regulating the turnover of various proteins. Proteins are fundamental to life for several reasons:
Important proteins in skin and the human body based on their overall impact and prevalence:
Dysfunction of the proteasome in skin cells can lead to various dermatological issues, including ▌accelerated aging of skin cells ▌reduced collagen production and increased breakdown ▌impaired elastin function ▌wrinkles, sagging and loss of elasticity ▌impaired wound healing and barrier function ▌increased susceptibility to UV damage and DNA damage [26] Or more skin conditions like:
PROTEASOME AND CELLULAR SENESCENCE The proteasome plays a crucial role in preventing cellular senescence, a state of permanent cell cycle arrest associated with aging:
PROTEASOME AND IMMUNE FUNCTION The proteasome is integral to immune system function:
Glycosylated proteins Proteins connected to sugar molecules, known as glycosylated proteins, can be targeted by the proteasome: ▌Ubiquitin-Proteasome System (UPS) is capable of degrading many types of glycoproteins [29]. ▌However, hyperglycemia (high blood sugar) can impair proteasome function. Glucose-derived compounds like methylglyoxal (MGO) can modify proteasome subunits, reducing their activity [29]. Amyloids The proteasome's relationship with amyloids (involved in for example Alzheimer's disease) is more complex. The proteasome can degrade some amyloid precursor proteins and smaller amyloid aggregates [30]. However, larger amyloid fibrils often overwhelm or inhibit the proteasome: ▌Amyloid aggregates can clog the entrance to the proteasome's catalytic core. ▌Some amyloids can directly inhibit proteasome activity. INFLUENCERS PROTEASOME ACTIVITY Challenges in protein clearance Several factors can hinder the proteasome's ability to clear modified or aggregated proteins: Glycation: Advanced glycation end products (AGEs) formed in hyperglycemic conditions can modify the proteasome, reducing its activity [29]. Oxidative stress: Often associated with aging and disease, it can damage both proteins and proteasomes [29]. Aging: Proteasome activity generally declines with age, reducing the cell's capacity to clear problematic proteins [30]. The proteasome's activity is sensitive to pH changes: ▌Optimal pH range for proteasome function is typically between 7.5-8.0. ▌Acidic conditions tend to inhibit proteasome activity, while alkaline conditions can enhance it to a certain extent. ▌Skin pH, which is typically slightly acidic (around 4.7-5.75), may influence extracellular proteasome activity. Oxidative stress has complex effects on the proteasome system in skin: ▌Mild oxidation (hormesis) can stimulate proteasomal degradation, while severe oxidation inhibits it ▌Oxidative stress can cause the 26S proteasome to disassemble into its 20S core and 19S regulatory components [25] ▌In skin, oxidative stress from UV radiation or environmental pollutants may affect proteasome function ▌Severely oxidized proteins may form non-degradable aggregates that can bind to and inhibit the proteasome [24] ▌Oxidative stress can reduce cellular ATP levels, affecting the ATP-dependent 26S proteasome function [25] ▌Oxidative stress can alter the association of chaperone proteins like HSP70 with the proteasome, affecting its function and assembly [25] Temperature can significantly impact proteasome function: ▌The optimal temperature for proteasome activity is typically around 37°C (human body temperature) [27] ▌Higher temperatures may initially increase proteasome activity but can eventually lead to denaturation and loss of function. ▌Low temperatures reduce proteasome activity by slowing down enzymatic reactions. ▌Skin, being exposed to environmental temperature changes, may experience fluctuations in proteasome activity. MAINTAIN AND IMPROVE PROTEASOME Several strategies can help maintain and improve proteasomal function: Exercise: Regular physical activity has been shown to enhance proteasome activity. Diet: ▌Protein: Ensuring adequate intake of high-quality proteins provides the building blocks for maintaining a healthy proteome ▌Polyphenols: Found in green tea, berries, and red wine, can stimulate proteasome function. ▌Omega-3 fatty acids: May help maintain proteasome activity and reduce oxidative stress. ▌Sulforaphane (found in broccoli sprouts): Activates Nrf2, which enhances proteasome function. ▌Spermidine: This natural polyamine has been shown to enhance autophagy and improve proteostasis. ▌Curcumin: This compound from turmeric has been shown to enhance proteostasis and have anti-aging effects ▌Caloric restriction or intermittent fasting: May enhance proteasome activity and promote cellular health. Stress management: Chronic stress can impair proteasome function, so stress reduction techniques will be beneficial. Sleep: Crucial for cellular repair and protein homeostasis. Skincare + ingredients: ▌Sun protection: Use broad-spectrum sunscreens to protect skin from photo-damage, which can impair proteasome function. ▌Retinoids: May enhance proteasome activity in skin cells. ▌Peptides: Certain peptides have been shown to stimulate proteasome function. ▌Licochalcone A: Activates Nrf2, which in turn enhances proteasome function. ▌Niacinamide: Supports proteasome function and improves skin barrier health. In-office treatments: ▌Low-level laser therapy: May improve proteasome function in skin cells. ▌Chemical peels: Can stimulate cellular renewal and potentially enhance proteasome activity. MISCELLANEOUS PROTEASOME FACTS ▌Ancient origins: Proteasomes are found in all three domains of life (bacteria, archaea, and eukaryotes), suggesting they evolved over 2 billion years ago. ▌Rapid recyclers: A single proteasome can degrade about 2 million proteins over its lifetime. ▌Circadian rhythm regulation: The proteasome plays a crucial role in maintaining our body's internal clock by degrading clock proteins at specific times. ▌Stress response: Under stress conditions, cells can form large assemblies of proteasomes called "proteasome storage granules" to quickly respond to changing protein degradation needs. The role of the proteasome in protein quality control, cellular regulation, interplay with autophagy, epigenetics, telomeres, cell senescence and more, makes it a key player in maintaining our health and beauty and an interesting target for new strategies to enhance longevity [28], health span and beauty span. Always consult a qualified healthcare professional to determine what the most suitable approach is for your needs and rejuvenation or regeneration goals. Take care! Anne-Marie References: [1] Glickman MH, Ciechanover A. Physiol Rev. 2002;82(2):373-428. [2] Lecker SH, et al. Annu Rev Biochem. 2006;75:629-649. [3] López-Otín C, et al. Cell. 2013;153(6):1194-1217. [4] Tanaka K. Proc Jpn Acad Ser B Phys Biol Sci. 2009;85(1):12-36. [5] Goldberg AL. Nature. 2003;426(6968):895-899. [6] Finley D. Annu Rev Biochem. 2009;78:477-513. [7] Pickart CM, Cohen RE. Nat Rev Mol Cell Biol. 2004;5(3):177-187. [8] Hershko A, Ciechanover A. Annu Rev Biochem. 1998;67:425-479. [9] Thrower JS, et al. EMBO J. 2000;19(1):94-102. [10] Smith DM, et al. Mol Cell. 2005;20(5):687-698. [11] Groll M, et al. Nature. 1997;386(6624):463-471. [12] Balch WE, et al. Science. 2008;319(5865):916-919. [13] Mizushima N, Komatsu M. Cell. 2011;147(4):728-741. [14] Dikic I. Trends Biochem Sci. 2017;42(11):873-886. [15] Ding WX, et al. Am J Pathol. 2007;171(2):513-524. [16] Zhao J, et al. Cell Metab. 2015;21(6):898-911. [17] Pandey UB, et al. Nature. 2007;447(7146):859-863. [18] Korolchuk VI, et al. Mol Cell. 2010;38(1):17-27. [19] Greer EL, Shi Y. Nat Rev Genet. 2012;13(5):343-357. [20] Qian MX, et al. Cell. 2013;153(5):1012-1024. [21] Muratani M, Tansey WP. Nat Rev Mol Cell Biol. 2003;4(3):192-201. [22] Gu B, Lee MG. Mol Cell. 2013;49(6):1134-1146. [23] Geng F, et al. Proc Natl Acad Sci USA. 2012;109(5):1437-1442. [24] Bach SV, et al. Biomol Concepts. 2016;7(4):215-227. doi:10.1515/bmc-2016-0016 [25] Bonea D, et al. BMC Plant Biol. 2021;21:486. doi:10.1186/s12870-021-03234-9 [26] Minoretti P, et al. Cureus. 2024;16(1):e52548. doi:10.7759/cureus.52548 [27] Groll M, et al. Nat Struct Biol. 2005;12(11):1062-1069. doi:10.1038/nsmb1006 [28] Galatidou S, et al. Mol Hum Reprod. 2024;30(7):gaae023. doi:10.1093/molehr/gaae023 [29=41] Queisser MA, et al. Hyperglycemia impairs proteasome function by methylglyoxal. Diabetes. 2010 [28=42] Mao, Y. Structure and Function of the 26S Proteasome. In: Harris, J.R., Marles-Wright, J. Macromolecular Protein Complexes III. Springer, 2021. [29=43] Schipper-Krom, S. Visualizing Proteasome Activity and Intracellular Localization. Front. Mol. Biosci. 6, 2019. [30=44] Lifespan.io. Loss of Proteostasis. Lifespan.io Topics. Accessed 2024.
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