Modulation of the ubiquitin-proteasome system by marine natural products

Abstract

The ubiquitin-proteasome system (UPS) is a key player in the maintenance of cellular protein homeostasis (proteostasis). Since proteasome function declines upon aging leading to the acceleration of its progression and the manifestation of age-related pathologies, many attempts have been performed towards proteasome activation as a strategy to promote healthspan and longevity. The marine environment hosts a plethora of organisms that produce a vast array of primary and secondary metabolites, the majority of which are unique, exhibiting a wide spectrum of biological activities. The fact that these biologically important compounds are also present in edible marine organisms has sparked the interest for elucidating their potential health-related applications. In this review, we focus on the antioxidant, anti-aging, anti-aggregation and anti-photoaging properties of various marine constituents. We further discuss representatives of marine compounds classes with regard to their potential (direct or indirect) action on UPS components that could serve as UPS modulators and exert beneficial effects on conditions such as oxidative stress, aging and age-related diseases.

Keywords: Anti-aggregation; Anti-aging; Anti-photoaging; Antioxidant; Marine natural products; Proteasome.

Graphical abstract

Fig. 1

The ubiquitin-dependent and ubiquitin-independent proteolysis. (a) The ubiquitin-dependent proteolysis is a three-step process that requires the presence of ubiquitin molecules and ATP consumption. E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme and E3 ubiquitin ligase enzyme are responsible for tagging the protein substrate with ubiquitin molecules. This process is repeated to generate a poly-ubiquitin chain, the standard form of which is tetra-ubiquitin. The ubiquitinated protein is recognized, unfolded and degraded by the 26S proteasome after the deubiquitinating enzymes (DUBs) remove the ubiquitin molecules from the protein substrate. The released free ubiquitin molecules will be used in another ubiquitination cycle. (b) Oxidatively modified proteins and partially or loosely unfolded proteins are degraded mainly by the 20S proteasome in a ubiquitin/ATP-independent manner.

Fig. 2

Marine classes of natural products and their major representatives. The illustrated marine compounds have been suggested to possess beneficial properties against aging, photoaging and age-related diseases.

Fig. 3

The antioxidant, anti-aging and anti-aggregation properties of marine-derived polysaccharides.

Fig. 4

The chemical structures of the marine-derived phlorotannins (a) eckol, (b) dieckol, and (c) phloroglucinol.

Fig. 5

The antioxidant, anti-aging and anti-aggregation properties of marine-derived phlorotannins.

Fig. 6

The antioxidant, anti-aging and anti-aggregation properties of marine-derived carotenoids.

Fig. 7

The chemical structures of marine-derived carotenoids (a) astaxanthin and (b) fucoxanthin.

Fig. 8

The photoprotective mechanisms of marine-derived compounds. Exposure to the sun, especially the solar UVA and UVB radiation, promotes reactive oxygen species (ROS) production that enhances DNA damage, lipid peroxidation and protein carbonylation, major causative factors of photoaging. Moreover, sun exposure stimulates the expression of several matrix metalloproteinases (MMPs) that result in increased collagen fibrils degradation contributing to photoaging. Marine-derived compounds (MAAs; Mycosporine-like amino acids, fucoidans, phlorotannins, and carotenoids) prevent photoaging through reduction of ROS generation and inhibition of MMPs expression. The extract from P. tricornutum stimulates proteasome activity resulting in decreased cellular levels of carbonylated and oxidatively damaged proteins. Consequently, marine-derived compounds alleviate photoaging markers leading to improvement of skin elasticity, smoothness and hydration, reduction of wrinkle formation, prevention of epidermal hypertrophy and inhibition of hyperpigmentation.

Fig. 9

The chemical structures of the marine-derived mycosporine-like amino acids (a) porphyra-334 and (b) shinorine.