Organelles are miscommunicating: Membrane contact sites getting hijacked by pathogens

Figures & data

Figure 1. The figure elucidates inter-organellar membrane contact sites (MCS) highlighting the interactions between different organelles within a cell.

Table 1. The table gives a snippet of MCS categorization alongside their example.

Type of MCS
Structural proteins	Hold two organelles together by forming a scaffold between the membrane of the organelles	Vesicle-Associated Membrane protein (VAMP)-associated protein (VAPs) Mdm1 tethering with Snx13 Oxysterol-Binding Protein (OSBP)-related protein 5 (ORP5) and ORP8 Extended-synaptotagmins (E-Syts)	ER and other organelles ER-Endolysosome [12] ER-endosome ER-PM [17]
Functional proteins	Helps in transport of essential biomolecules like lipids,proteins,metabolites and even small ions.	Lam6 Kv2.1	Mitochondria-ER [13] Mitochondria-ER [14]
Regulatory proteins	Control the distance and functionality of the MCS	p53	Mitochondria-ER Mitochondria-vacuoles [15]
Sorter/recruitment proteins	Specify the lipidome and proteome associated with a particular contact site.Recruit resident contact proteins and repel non-residents.	PACS-2 Rab32 PI kinases and phosphatases	ER-Mitochondria [16] ER-Mitochondria Miscellaneous contacts [18]

Figure 2. The figure illustrates bacteria-induced membrane contact sites demonstrating how bacteria establish close interactions between host cell organelles to promote their replication.

Figure 3. MCS between virus-induced replication organelles and cellular organelles.

Table 2. The table summarizes all inhibitors that act on specialized MCS components that might be essential for dug targeting such that the MCS formed between the host organelle and the inclusion bodies can be successfully targeted and obliterated such that the pathogens cannot evade the immune system.

MCS Component	Chemical	Mode of action	Reference
OSBP	TTP-8307	Disorders the lipid shuttling function of OSBP directly By targeting the ORD (OSBP-related ligand binding domain).It also inhibits replication by targeting the PI4KIIIβ-PI4P-OSBP pathway.	[90]
	OSW-1	OSW-1 reduces the intracellular OSBP level by inhibiting intracellular pathogen replication (e.g. +RNA virus).It also inhibits PI4P shuttling which is required for pathogen survival.	[91]
	Itraconazole (ITZ)	ITZ prevents PI4P removal from the Golgi, leading to a build-up of both PI4P and OSBP at ER-Golgi MCS.	[73]
	(Enviroxmine like compound)T-00127-HEV2 (THEV)	THEV inhibits the binding of 25-hydroxycholesterol (25-OHC) to OSBP which is required for its activity.	[92]
STIM, Orai	MG-132	It is a proteasome inhibitor that promotes autophagy-mediated degradation of STIM.	[93]
	GSK-7975A	Alters Ca^2+ influx thereby acting as a Orai antagonist.	[94]
	CM_128	Inhibits Orai followed by desensitizing STIM. It activates Ca^2+ currents, in a concentration-dependent manner.	[95]
CERT	HPA-12	It binds to the ceramide-binding pocket in the CERT START domain, thereby acting as a competitive antagonist and thus blocking the synthesis of sphingomyelin and is speculated to represent a novel drug prototype.	[96]
	(1S, 2R)-HPCB-5	Novel drug that inhibits sphingomyelin synthesis. It also helps differentiate on and off target effects when CERT is pharmacologically inhibited.	[97]

Henne WM, Zhu L, Balogi Z, et al. Mdm1/Snx13 is a novel ER-endolysosomal interorganelle tethering protein. J Cell Bio. 2015 Aug 17;210(4):541–551. doi: 10.1083/jcb.201503088. PubMed PMID: 26283797; PubMed Central PMCID: PMCPMC4539980.

 PubMed Web of Science ®Google Scholar

Giordano F, Saheki Y, Idevall-Hagren O, et al. PI(4,5)P(2)-dependent and Ca(2+)-regulated ER-PM interactions mediated by the extended synaptotagmins. Cell. 2013Jun 20;153(7):1494–1509. doi: 10.1016/j.cell.2013.05.026. PubMed PMID: 23791178; PubMed Central PMCID: PMCPMC3716012.

 PubMed Web of Science ®Google Scholar

Gatta AT, Wong LH, Sere YY, et al. A new family of StART domain proteins at membrane contact sites has a role in ER-PM sterol transport. Elife. 2015 May 22;4. doi: 10.7554/eLife.07253. PubMed PMID: 26001273; PubMed Central PMCID: PMCPMC4463742.

 PubMed Web of Science ®Google Scholar

Johnson B, Leek AN, Solé L, et al. Kv2 potassium channels form endoplasmic reticulum/plasma membrane junctions via interaction with VAPA and VAPB. Proc Natl Acad Sci U S A. 2018;115(31):E7331–E7340. doi: 10.1073/pnas.1805757115

 PubMed Web of Science ®Google Scholar

Scorrano L, De Matteis MA, Emr S, et al. Coming together to define membrane contact sites. Nat Commun. 2019;10(1):1287. doi: 10.1038/s41467-019-09253-3

 PubMedGoogle Scholar

Raturi A, Simmen T. Where the endoplasmic reticulum and the mitochondrion tie the knot: the mitochondria-associated membrane (MAM). Biochim Biophys Acta. Biochim Biophys Acta, Mol Cell Res. 2013;1833(1):213–224. doi: 10.1016/j.bbamcr.2012.04.013

 PubMed Web of Science ®Google Scholar

Raiborg C, Wenzel E, Pedersen N, et al. Phosphoinositides in membrane contact sites. Biochem Soc Trans. 2016;44(2):425–430. doi: 10.1042/BST20150190

 PubMedGoogle Scholar

Albulescu L, Bigay J, Biswas B, et al. Uncovering oxysterol-binding protein (OSBP) as a target of the anti-enteroviral compound TTP-8307. Antiviral Res. 2017;140:37–44. doi: 10.1016/j.antiviral.2017.01.008

 PubMed Web of Science ®Google Scholar

Albulescu L, Strating JRPM, Thibaut HJ, et al. Broad-range inhibition of enterovirus replication by OSW-1, a natural compound targeting OSBP. Antiviral Res. 2015;117:110–114. doi: 10.1016/j.antiviral.2015.02.013

 PubMed Web of Science ®Google Scholar

Strating JR, van der Linden L, Albulescu L, et al. Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein. Cell Rep. 2015 Feb 3;10(4):600–615. doi: 10.1016/j.celrep.2014.12.054. PubMed PMID: 25640182; PubMed Central PMCID: PMCPMC4383725.

 PubMed Web of Science ®Google Scholar

Arita M, Kojima H, Nagano T, et al. Oxysterol-binding protein family I is the target of minor enviroxime-like compounds. J Virol. 2013;87(8):4252–4260. doi: 10.1128/JVI.03546-12

 PubMed Web of Science ®Google Scholar

Kuang XL, Liu Y, Chang Y, et al. Inhibition of store-operated calcium entry by sub-lethal levels of proteasome inhibition is associated with STIM1/STIM2 degradation. Cell Calcium. 2016;59(4):172–180. doi: 10.1016/j.ceca.2016.01.007

 PubMed Web of Science ®Google Scholar

Petit A, Knabe L, Khelloufi K, et al. Bronchial epithelial calcium metabolism impairment in smokers and chronic obstructive pulmonary disease. Decreased ORAI3 signaling. Am J Respir Cell Mol Biol. 2019;61(4):501–511. doi: 10.1165/rcmb.2018-0228OC

 PubMed Web of Science ®Google Scholar

Wen L, Voronina S, Javed MA Inhibitors of ORAI1 prevent cytosolic calcium-associated Injury of Human Pancreatic Acinar cells and acute pancreatitis in 3 mouse models. Gastroenterology. 2015;149(2):481–92 e7. doi: 10.1053/j.gastro.2015.04.015

 PubMed Web of Science ®Google Scholar

Bandet CL, Hajduch E. CERT-Dependent ceramide transport, a crucial process in cells. Diabetes Clin Res. 2021;3(2):40–45.

 Google Scholar

Hanada K, Sakai S, Kumagai K. et al. Natural ligand-mimetic and nonmimetic inhibitors of the ceramide transport protein CERT. Int J Mol Sci. 2022;23(4). doi: 10.3390/ijms23042098

 Web of Science ®Google Scholar

Data availability statement

No data sets were analysed in the manuscript and thus availability is not applicable.