Mpp1-KO Mouse

MPP1, also known as membrane palmitoylated protein 1/p55, belongs to the MAGUK (membrane-associated guanylate kinase homolog) family. It is a major target of palmitoylation in red blood cell (RBC) membranes. In erythroid cells, it is crucial for the formation of the junctional complex of the erythrocyte membrane skeleton. Additionally, it is involved in organizing membrane raft microdomains, which are important for organizing signaling partners into functional complexes [1].

In erythroid cells, MPP1 directly interacts with flotillins (raft-marker proteins), forming high-affinity complexes via a region within the D5 domain of MPP1. These interactions are key for the dynamic nanoscale organization of raft domains in the plasma membrane. Overexpression of peptides containing the "flotillin binding motif" inhibits the endogenous MPP1-flotillin interaction, causing lateral disorganization of raft domains, reduction in plasma membrane order, and decreased activation of the raft-dependent insulin receptor pathway [3]. Also, MPP1 acts as a key raft-capturing molecule, regulating the temporal immobilization of flotillin-based nanoclusters and controlling the local concentration and confinement of sphingomyelin and Thy-1 in raft nanodomains [2]. Moreover, MPP1 has been identified as a heart-failure-promoting protein. In cardiac transcriptome data of different heart failure models, MPP1 was up-regulated. MPP1-transgenic mice showed symptoms of heart failure, with reduced left ventricular ejection fraction, cardiac enlargement, and dilation. MPP1 can increase the levels of the angiotensin II AT1 receptor (AGTR1), which has a heart-failure-promoting function [4].

In conclusion, MPP1 has essential functions in the organization of membrane raft microdomains in erythroid cells, likely through its interactions with flotillins. In addition, it plays a role in heart failure pathogenesis as its up-regulation can promote heart failure symptoms, possibly by increasing AGTR1 levels. The study of MPP1 in model systems, such as transgenic mice, has provided insights into its role in these biological processes and disease conditions.

References:

1. Trybus, Magdalena, Niemiec, Lukasz, Biernatowska, Agnieszka, Hryniewicz-Jankowska, Anita, Sikorski, Aleksander F. 2019. MPP1-based mechanism of resting state raft organization in the plasma membrane. Is it a general or specialized mechanism in erythroid cells? In Folia histochemica et cytobiologica, 57, 43-55. doi:10.5603/FHC.a2019.0007. https://pubmed.ncbi.nlm.nih.gov/31099889/

2. Biernatowska, Agnieszka, Wójtowicz, Karolina, Trombik, Tomasz, Sikorski, Aleksander F, Czogalla, Aleksander. 2022. MPP1 Determines the Mobility of Flotillins and Controls the Confinement of Raft-Associated Molecules. In Cells, 11, . doi:10.3390/cells11030311. https://pubmed.ncbi.nlm.nih.gov/35159121/

3. Biernatowska, Agnieszka, Olszewska, Paulina, Grzymajło, Krzysztof, Sikorski, Aleksander F, Czogalla, Aleksander. 2021. Molecular characterization of direct interactions between MPP1 and flotillins. In Scientific reports, 11, 14751. doi:10.1038/s41598-021-93982-3. https://pubmed.ncbi.nlm.nih.gov/34285255/

4. Alla, Joshua Abd, Nerger, Eric, Langer, Andreas, Quitterer, Ursula. 2023. Identification of membrane palmitoylated protein 1 (MPP1) as a heart-failure-promoting protein triggered by cardiovascular risk factors and aging. In Biochemical pharmacology, 217, 115789. doi:10.1016/j.bcp.2023.115789. https://pubmed.ncbi.nlm.nih.gov/37683843/