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Tylosis with Esophageal Cancer
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Linkage mapping and targeted next-generation sequencing studies have identified gain-of-function (GOF) mutations (p.I186T, p.P189L, and p.D188N) in the human rhomboid family protein RHBDF2 (or inactive rhomboid protease iRhom), which is encoded by the RHBDF2 gene on 17q25.1, and which is involved in epidermal growth factor receptor (EGFR) shedding [9].
Misconnecting the dots: altered mitochondrial protein-protein interactions and their role in neurodegenerative disorders
Published in Expert Review of Proteomics, 2020
Mara Zilocchi, Mohamed Taha Moutaoufik, Matthew Jessulat, Sadhna Phanse, Khaled A. Aly, Mohan Babu
Besides mt biogenesis, one of the most well characterized pathways for mt dynamics is the PINK1-Parkin mitophagy (i.e. lysosomal degradation of impaired mt [11]) pathway. Under physiological conditions, PINK1 is synthesized in cytosol and imported into IMM through the translocases of the inner and outer membranes (TIMM and TOMM) in a membrane potential-dependent manner [11]. In the IMM, PINK1 is cleaved by several mt proteases, such as mt processing peptidase (MPP) and rhomboid protease of the IMM (PARL), and further degraded by the proteasome. Therefore, endogenous PINK1 levels are kept at minimum, preventing mitophagy of polarized mt [11]. In contrast and when mt lose their membrane potential, PINK1 accumulates onto the OMM and phosphorylates MFN2 and VDACs, thus recruiting Parkin [101,102]. PINK1-activated Parkin then ubiquitinates OMM proteins to inhibit mt fusion and motility ([103]; Figure 2(e)). Recently, a small accessary protein of the TOMM complex, TOMM7, was found to be vital for PINK1 OMM accumulation. This is because PINK1 mutation or deletion of TOMM7 that failed PINK1 to accumulate at the OMM was instead imported into depolarized mt and cleaved by the mt metalloprotease, OMA1. Mt import arrest observed in some PD patients with PINK1 mutations was rescued by OMA1 suppression, implicating a likely druggable target for PD [104].
Toxoplasma gondii infection: novel emerging therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2023
Joachim Müller, Andrew Hemphill
Like other organisms [110], T. gondii harbors serine, cysteine, metallo and aspartylproteases involved in a variety of physiological processes. Serine proteases, in particular subtilisin and rhomboid family enzymes, are involved in invasion and egress [111] as evidenced by inhibitor studies [112]. Moreover, the microneme rhomboid protease TgROM1 is essential for intracellular proliferation, as evidenced by the conditional knock-out [113]. Other ROM proteases, in particular ROM4, are involved in the host cell invasion [114]. The secreted microneme proteins MIC2, MIC4, and M2AP are processed by the subtilisin TgSUB1, as shown by knock-out plus complementation [115]. Other proteases involved in microneme and rhoptry protein maturation are cysteine proteases belonging to the family of cathepsins [116]. Therefore, it is not surprising that serine and cysteine protease inhibitors have detrimental effects on microneme secretion and host cell invasion [117,118]. Other proteases include the rhoptry protease toxolysin-1, a metalloprotease [119] and aspartylproteases. The aspartylproteases of T. gondii belong to five families. TgASP1 is associated to the inner membrane complex, but is not essential, as shown by knock-out [120]. The situation is different with ASP5. This protease is located in the Golgi and processes effector proteins excreted to the host cell. Consequently, the knock-out of ASP5 decreases virulence [121]. ASP5 is essential for the cleavage of the GRA family proteins 16, 19, and 20 and involved in the correct targeting of GRA16 and 24 to the host cell nucleus [122,123]. Recent investigations suggest that the treatment of mice with aspartylprotease inhibitors developed against the HIV enzyme reduced the parasite burden in a mouse model for chronic T. gondii infection [124].