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Dietary Influence on Muscle Protein Synthesis and Hypertrophy
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
James McKendry, Stuart M. Phillips
AAs are fundamental in driving increased MPS via mTORC1 activity, though, again, determining the mechanisms through which AAs drive increased rates of MPS has been somewhat elusive. Increased circulating concentrations of AAs following digestion and absorption of protein are transported into skeletal muscle. The L-type amino acid transporter 1 (LAT1) plays a vital role in transporting AAs, mainly the branched-chain amino acid (BCAA) leucine, into skeletal muscle (57). Once inside the muscle, AAs influence mTORC1 activity via conversion of the Rag GTPases (Rag A/B and Rag C/D) to a nucleotide-bound state and association with the Ragulator complex, which subsequently binds directly to Raptor and facilitates the recruitment of mTORC1 to the lysosomal surface, increasing mTORC1 kinase activity. Conversely, the absence of AAs results in mTORC1 dissociating from the lysosomal membrane, preventing the essential interactions with co-activators (69). AAs also augment mTORC1 activity via human vacuolar protein sorting 34 (VPS34) and a calcium (Ca2+)/calmodulin (CaM)–dependent interaction (51). Building on these important discoveries, mTORC1 has been shown to “sense” AAs through two distinct mechanisms: vacuolar H+–adenosine triphosphatase ATPase (v-ATPase) (117) and GATOR 1–, GATOR 2–, and Sestrin2-mediated regulation (11, 25), both of which act via Rag GTPases and the Ragulator complex. Leucyl-tRNA synthetase (LeuRS) has been proposed as another candidate contributing to the AA sensing mechanism (61), though much work is still required to fully elucidate the AA-mediated mTORC1 activity.
Characteristics, Events, and Stages in Tumorigenesis
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
Tumor-derived extracellular vesicles (TEVs) released from cancer cell types serve to orchestrate fundamental processes involved in tumorigenesis [840]. Inward budding within the endosomal/lysosomal pathway along with the fusion of multivesicular bodies (MVBs) with the plasma membrane gives rise to TEVs [840]. A series of complex molecular machinery orchestrates various processes of biogenesis, including MVBs/intraluminal vesicle (ILV) biogenesis, cargo sorting, membrane invagination, and the release of exosomes, respectively [840]. Some of the identified molecules involved in these machineries are the small Rab GTPase family (e.g., Rab11, Rab27, and Rab35), endosomal sorting complex required for transport (ESCRT -0, -I, -II, and -III), ceramide-generating sphingomyelinase, vacuolar protein-sorting 4 homolog A (VPS4A), accessory proteins (Alix, and VTA-1), tetraspanin-mediated organization of specific proteins (amyloidogenic protein premelanosome protein (PMEL)), ceramide synthesis to induce vesicle curvature and budding, and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) system [828, 830, 831, 840, 855, 896, 899, 902–915]. In addition, the amount of cholesterol or enrichment of lysobisphosphatidic acid and intracellular calcium changes are also believed to be involved in this regulation process [830, 840, 849, 916]. ‘Apoptotic bodies', a term coined by Kerr in 1972, are large EVs with a broad diameter shed by the plasma membrane of apoptotic cells containing mostly fragmented subcellular organelles for degradation, and they are picked up by phagocytic cells for digestion [851, 857, 898, 900, 917–920]. Therefore, these EVs are not involved in intercellular communication [857].
Hepatitis E Virus
Published in Dongyou Liu, Laboratory Models for Foodborne Infections, 2017
Kavita Lole, Prudhvi Lal Bhukya, Subhashis Chatterjee
Once viral RNA is released in the cytosol, ORF1 translation is initiated by the cap-dependent recruitment of ribosomes. It is not clear whether the ORF1 encoded nonstructural polyprotein functions as a single protein or whether it is processed into individual functional units. However, the regions predicted to encode viral methyltransferase, helicase, and RdRp produce functionally active proteins when expressed in heterologous systems. The genomic RNA is copied into a negative-sense RNA intermediate by viral RdRp. These RNA intermediates then serve as templates for the synthesis of genomic as well as subgenomic positive-sense RNA species. Genomic intermediates have been detected in replicon-transfected cells220 in the livers of experimentally infected macaques252 and pigs.155 It was demonstrated using a replicon system that there is an alternate cycle of positive- and negative-sense RNA synthesis.253 Single subgenomic RNA is translated to synthesize ORF2 and ORF3 proteins.210,211,245 The ORF2 protein packages the genomic positive-sense RNA into progeny virions. Immunocapture PCR analysis showed the association of ORF3 on the surface of the cell-culture-generated HEV, which also showed a lower density than the ORF3 deficient virus. These observations suggested that the ORF3 protein is present on the virion surface in association with cellular lipids and probably plays some role during viral egress.254 Emerson et al.243 and Nagashima et al.255 have documented the importance of the PSAP motif within the P2 domain of the ORF3 protein in the virus egress and the probable role of SRC homology 3 signaling pathways in HEV maturation and egress. PSAP motif is required for the formation of membrane-associated HEV particles with ORF3 on their surface, which is mediated by cellular Tsg101 protein.256,257 These findings suggest that HEV follows the vacuolar protein sorting pathway and uses cellular proteins such as Tsg101 for its release from infected cells.
Cell cycle deregulation in neurodegenerative diseases
Published in International Journal of Neuroscience, 2023
Xiaobo Zhang, Shuxin Song, Wenpeng Peng
This may provide us a new therapy of AD. Lee’s [49] results demonstrated that Aβ efficiently stimulated the mTORC1 signaling pathway to facilitate HIF1α synthesis and autophagy inhibition. Thus it promoted the expression of cell cycle regulatory proteins, during which CDK2 uniquely stimulates tau phosphorylation for micro-tubule destabilization-mediated neuronal apoptosis. Also, it has been shown that the vacuolar protein sorting 34 (Vps34) complex, which belongs to the class III phosphatidylinositol3 (PtdIns3) kinases, interacted with Beclin1 to regulate the production of PtdIns3P and autophagy. CDK1-mediated phosphorylation of Thr159 in Vps34 negatively regulated its interaction with Beclin 1 during mitosis. CDK5⁄p25, could also phosphorylate Thr159 of Vps34. Hence, it was suggested that phosphorylation of Thr159 in Vps34 by CDK1 and CDK5⁄p25, was a key regulatory mechanism in AD [50].
Protein misfolding, ER stress and chaperones: an approach to develop chaperone-based therapeutics for Alzheimer’s disease
Published in International Journal of Neuroscience, 2023
Rimaljot Singh, Navpreet Kaur, Neelima Dhingra, Tanzeer Kaur
As per a recent study, the vacuolar protein sorting 35 (VPS35) is a main component of the retromer complex system, a ubiquitous multiprotein assembly responsible for the sorting and trafficking of protein cargos from endosomes. VPS35 can regulate APP metabolism and Aβ formation and its levels are reduced in AD. Prolonged administration of TPT-172, a pharmacological chaperone has shown to upregulate the VPS35 levels. This improvement of retromer activity by pharmacological chaperone positively affects many of the major phenotypic aspects of AD: memory loss, synapse, Aβ and tau pathology, and neuroinflammation [130].
How can we turn the PI3K/AKT/mTOR pathway down? Insights into inhibition and treatment of cancer
Published in Expert Review of Anticancer Therapy, 2021
Said M. Afify, Aung Ko Ko Oo, Ghmkin Hassan, Akimasa Seno, Masaharu Seno
Class III PI3K has Vps34 encoded by PIK3C3, which is comprised of the catalytic subunit and a C2 domain. The regulatory subunit is vacuolar protein sorting 15 (Vps15, or p150) encoded by PIK3R4 (Figure 1). Vps34 only produces PI(3)P, an essential regulator of membrane trafficking, and is considered as a nutrient-regulated lipid kinase which mediates signaling through mTOR, showing a prospective role in regulating cell growth [27]. The Class III PI3K family has been demonstrated to mediate autophagy, membrane trafficking, and AMPK-dependent insulin sensitivity [28–31].