Daniel G. S. Capelluto
Cecilia B. Conde
David A. Tumbarello
Geert van den Bogaart4- 1Protein Signaling Domains Laboratory, Department of Biological Sciences, Fralin Life Sciences Institute, and Center for Soft Matter and Biological Physics, Virginia Tech, Blacksburg, VA, United States
- 2Medical Research Institute Mercedes and Martín Ferreyra (INIMEC-CONICET-UNC), Córdoba, Argentina
- 3Biological Sciences, University of Southampton, Southampton, United Kingdom
- 4Groningen Biomolecular Science and Biotechnology Institute (GBB), University of Groningen, Groningen, Netherlands
Editorial on the Research Topic
Signaling Proteins for Endosomal and Lysosomal Function
Cells control their activity, in coordination with signal cues, by modulating the levels of plasma membrane receptors and transporters by the action of endosomes and lysosomes. This process is initiated by ubiquitination of cell surface receptors and transporters (cargoes), followed by their internalization by endocytosis. These cargoes are then transported via vesicular trafficking to early endosomes and, depending on external cues, they are either recycled back to the plasma membrane or degraded in late endosomal or lysosomal compartments. Given the heterogeneity of endosomes and lysosomes, due to their specific protein and lipid composition, subcellular localization, and membrane shape, it is not surprising they have also arisen as dynamic signaling platforms. Endosomes and lysosomes elicit an array of signaling events, including regulation of gene expression, cell survival, cytoskeletal organization, nutrient uptake, lipid transport, and autophagy (Lefebvre et al., 2018; Norris and Grant, 2020; Yang and Wang, 2021). These organelles can also be hijacked by pathogen effector proteins, facilitating pathogen survival (Asrat et al., 2014).
In this research topic, we assembled review and original research articles that provide recent advances of molecular mechanisms that are a signature for endosomal and lysosomal function under physiological and pathological conditions. We envision that these articles will illustrate a thorough overview of the current progress and future directions relying on proposed mechanistic models.
Peripheral signaling and trafficking proteins target endosomal and lysosomal compartments through interactions with phosphoinositides. One of the best studied phosphoinositide-binding domains is the PX domain, which displays a wide range of specificities for these lipids. Kervin et al. present an elegant meta-analysis that demonstrates that binding of PX domain-containing proteins to membranes is regulated by modification on lysine and arginine residues of PX domains. These side chain modifications, such as acetylation, methylation, malonylation, succinylation, hydroxysobutyrylation, and glycation, neutralize the positive charges on lysine and arginine residues, thus, impairing electrostatic interactions with phosphoinositides. These modifications on PX domains, named MET-stops, are also predicted to interfere with “hot spot” sequences for membrane association as identified by the Membrane Optimal Docking Area algorithm. Therefore, MET-stops represent erasers of protein membrane targeting.
Cargo trafficking relies on the function of the cargo sorting machinery known as ESCRT (Migliano and Teis, 2018). Roach et al. provide a detailed review on the function of the endosomal ESCRT protein TOM1 in physiological and disease scenarios. TOM1 participates in cargo trafficking in coordination with other ESCRT proteins and phosphoinositides. TOM1 is also involved in other cellular functions, including autophagy, immune responses, neurodegeneration, and cancer, although many questions regarding molecular interactions in these processes and crosstalk with TOM1’s endosomal function still remain unanswered. Recently, TOM1 has been shown to be hijacked under Shigella flexneri infection following accumulation of intracellular phosphatidylinositol 5-phosphate, in which the ESCRT function of TOM1 is impaired. We hope that more research will shed light on the molecular mechanisms governing TOM1 function in these processes.
Schmidt-Arras and Rose-John review the complex spatial regulation of signaling in response to the pro-inflammatory cytokine interleukin 6 (IL-6). The IL-6 receptor consists of the IL-6-binding subunit α and the signaling subunit gp130, which is shared among many different cytokines. The trafficking of the receptors to endosomes and lysosomes is an important layer of regulation. Following endocytosis of the IL-6 receptor-IL-6 complex, signaling can continue from within the lumen of endosomal compartments. Moreover, the receptor can be recycled to the plasma membrane, but also targeted to lysosomes for its degradation. As summarized by Schmidt-Arras and Rose-John, mutations that disrupt endo/lysosomal IL-6 receptor trafficking are a cause for disease.
Dabral and van den Bogaart review the roles of phospholipase 2 (PLA2) in phagocytosis. Phagocytosis is mechanistically related to receptor-mediated endocytosis, and is the process by which immune cells, such as macrophages and neutrophils, ingest pathogens and subsequently kill them in phago-lysosomes. PLA2 is a family of enzymes that hydrolyzes phospholipids, producing a free fatty acid and a lysolipid. In addition to the canonical role of PLA2 in eicosanoid signaling (Soberman and Christmas, 2003), various PLA2 forms play specific roles in endolysosomal function. For instance, the cleavage of lipids by certain PLA2s alters intrinsic membrane curvature, and thereby facilitates the remodeling of the membrane for particle uptake. Similarly, PLA2s play a role in the repairing of membranes to maintain the integrity of endolysosomal compartments.
Trnka et al. present data showing that the protein FUS (Fused in Sarcoma) clusters lysosomes. FUS is an RNA-binding protein involved in regulation of transcription, RNA splicing, and RNA transport (Yamaguchi and Takanashi, 2016). However, mutations in FUS have been related to familial forms of the progressive neurodegenerative disease amyotrophic lateral sclerosis (ALS) (Kwiatkowski et al., 2009). Trnka et al. hypothesized that FUS might affect lysosomal function, since other familial forms of ALS are due to alterations in genes involved in the function of lysosomes and impaired lysosome trafficking has been reported in ALS post-mortem tissue (Root et al., 2021). Indeed, Trnka et al. found that FUS forms cytosolic aggregates in a concentration-dependent fashion and that lysosomes accumulate next to these aggregates.
Acidification within the endosomal pathway is a crucial step to ensure organelle identity, cargo sorting, vesicle fusion, and lysosomal activity. This process is primarily driven by the vacuolar ATPase (V-ATPase), which uses ATP hydrolysis to drive the translocation of hydrogen ions across endosomal and lysosomal membranes resulting in a reduction in lumenal pH. Jaskolka et al. provide a thorough analysis of the yeast RAVE and mammalian Rabconnectin-3 complexes, which have essential roles in the regulation of V-ATPase assembly and organelle acidification. Our understanding of RAVE function and the complex mechanisms associated with V-ATPase assembly in yeast has provided much needed insight into Rabconnectin-3 function in higher eukaryotes, although as highlighted in this review, there are still many open questions. Regardless, it has now become apparent that Rabconnectin-3, via its regulation of V-ATPase activity, is an essential player in a variety of intracellular activities including cargo transport and control of signaling along the endocytic route.
In summary, this collection of articles for the Research Topic Signaling Proteins for Endosomal and Lysosomal Function provides a more comprehensive understanding of several aspects of the endosomal and lysosomal functions, which will serve as a platform for novel discoveries in these intriguing organelles.
Author Contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Asrat, S., de Jesús, D. A., Hempstead, A. D., Ramabhadran, V., and Isberg, R. R. (2014). Bacterial Pathogen Manipulation of Host Membrane Trafficking. Annu. Rev. Cell Dev. Biol. 30, 79–109. Epub 20140806. doi:10.1146/annurev-cellbio-100913-013439
Kwiatkowski, T. J., Bosco, D. A., Leclerc, A. L., Tamrazian, E., Vanderburg, C. R., Russ, C., et al. (2009). Mutations in the FUS/TLS Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis. Science. 323 (323), 1205–1208. doi:10.1126/science.1166066
Lefebvre, C., Legouis, R., and Culetto, E. (2018). ESCRT and Autophagies: Endosomal Functions and Beyond. Semin. Cell Developmental Biol. 74, 21–28. Epub 20170812. doi:10.1016/j.semcdb.2017.08.014
Migliano, S. M., and Teis, D. (2018). ESCRT and Membrane Protein Ubiquitination. Prog. Mol. Subcell Biol. 57, 107–135. doi:10.1007/978-3-319-96704-2_4
Norris, A., and Grant, B. D. (2020). Endosomal Microdomains: Formation and Function. Curr. Opin. Cell Biol. 65, 86–95. Epub 20200401. doi:10.1016/j.ceb.2020.02.018
Root, J., Merino, P., Nuckols, A., Johnson, M., and Kukar, T. (2021). Lysosome Dysfunction as a Cause of Neurodegenerative Diseases: Lessons From Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. Neurobiol. Dis. 154, 105360. Epub 20210331. doi:10.1016/j.nbd.2021.105360
Soberman, R. J., and Christmas, P. (2003). The Organization and Consequences of Eicosanoid Signaling. J. Clin. Invest. 111, 1107–1113. doi:10.1172/jci200318338
Yamaguchi, A., and Takanashi, K. (2016). FUS Interacts With Nuclear Matrix-Associated Protein SAFB1 as Well as Matrin3 to Regulate Splicing and Ligand-Mediated Transcription. Sci. Rep. 6 (6), 35195. Epub 20161012. doi:10.1038/srep35195
Keywords: PX domains, TOM1, PLA2, IL6-receptor, FUS, v-ATPase, endosomes, lysosomes
Citation: Capelluto DGS, Conde CB, Tumbarello DA and van den Bogaart G (2021) Editorial: Signaling Proteins for Endosomal and Lysosomal Function. Front. Cell Dev. Biol. 9:821719. doi: 10.3389/fcell.2021.821719
Received: 24 November 2021; Accepted: 26 November 2021;
Published: 16 December 2021.
Edited and reviewed by:
Ana Cuenda, Spanish National Research Council (CSIC), SpainCopyright © 2021 Capelluto, Conde, Tumbarello and van den Bogaart. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Daniel G. S. Capelluto, Y2FwZWxsdXRAdnQuZWR1