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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:
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.
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:
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:
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:
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:
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:
Oxidative stress has complex effects on the proteasome system in skin:
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:
Adequate sleep: Crucial for cellular repair and protein homeostasis. Skincare + ingredients:
MISCELLANEOUS PROTEASOME FACTS
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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