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Heme Oxygenase-1 in Kidney Health and Disease
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Pu Duann, Elias A. Lianos, Pei-Hui Lin
The signal peptide peptidase (SPP), a member of aspartyl protease family 42 kDa glycoprotein located in the ER membrane, catalyzes proteolysis of many tail-anchored ER proteins including HO-1 (74,75). Under hypoxic condition, HO-1 (but not HO-2) undergoes SPP-mediated intramembrane cleavage which resulted in HO-1 cytosolic and nuclear translocation, a step independent of HO-1 catalytic activity (75,76) (Figure 2A and B). The SPP cleavage site was identified between a conserved F275 and L276 dipeptide within its C-terminal 23 amino acid membrane anchor sequence (75,77) (Figure 2B). Full cleavage by SPP and the subsequent nuclear translocation also relies on the neighboring degradation signal sequence (PEST domain, amino acids 239–254) and a leucine-rich region of nuclear shuttle sequence (amino acids 207–221) in HO-1 (75).
Genetics of Psoriasis and Psoriatic Arthritis
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
Other psoriasis susceptibility genes identified in GWASs in patients of European and Chinese origin include HCP5 (rs2395029), which had the strongest association in one study [70], and has no known function but is associated with a low viral set point in HIV infection; genes called lipoma HMGIC fusion partner (LHFP), and conserved oligomeric Golgi complex component 6 (COG6) on chromosome 13q13; signal peptide peptidase-like 2a (SPPL2A); loci on 15q21 [70] and 3p24; IL28RA; REL; IFIH1; ERAP1; TRAF3IP2; NFKBIA; TYK2 [72]; interleukin 23 receptor subunit (IL23R); p19 subunit of IL23 (IL23A); IL13; TNIP1; TNFAIP3; ZNF313 [72]; CDKAL1; PTPN22; and ADAM33 [82]. Several of these associations have been replicated in independent studies, including IL23R, IL23A, TNFAIP3, TNIP [83], IL13 [48], and TRAF3IP2 [84]. Meta-analysis of two GWASs and subsequent replication in three independent cohorts identified additional psoriasis susceptibility loci at NOS2, FBXL19, PSMA6-NFKBIA, and RNF114 [48,84,85]. A multistage replication study of the Chinese GWAS also identified additional susceptibility loci at PTTG1, CSMD1, GJB2, SERPINB8, and ZNF816A, although only ZNF816A and GJB2 showed evidence for association with the German replication cohort, which did not hold when combined with an American replication cohort [83].
Signal peptide peptidase: a potential therapeutic target for parasitic and viral infections
Published in Expert Opinion on Therapeutic Targets, 2022
Christopher Schwake, Michael Hyon, Athar H. Chishti
Signal peptide peptidase is an evolutionarily conserved aspartyl protease required for normal cell homeostasis through clearance of accumulated signal peptides in the ER. While much attention has been given to this class of enzymes, as well as the closely related presenilins, the potential for targeting of these enzymes in pathogenic infections is a promising area of future research. The major parasite pathogens of humans each encode a single SPP gene that has been demonstrated to be an effective target in Plasmodium, Babesia, Trypanosoma, and Leishmania infections (Figure 5A). Furthermore, extension of SPP inhibition with HIV protease inhibitors showed further promise in treating Leishmaniasis. Biochemical validation of SPP activity in the parasites will aid development of parasite-specific SPP inhibitors. In contrast, the viral pathogens utilize host SPP to complete their lifecycles. Prevalent infections with HCV and HSV-1 make these viral pathogens attractive targets due to the chronic nature of infection and emergence of drug-resistant genotypes. A balance needs to be achieved in reducing host toxicity resulting from inhibition SPP while selectively impacting viral replication significantly. Further development of complex-specific inhibitors of SPP should be prioritized for taking advantage of this novel pathway for infection control with broad global implications.
T cells specific for a TAP-independent self-peptide remain naïve in tumor-bearing mice and are fully exploitable for therapy
Published in OncoImmunology, 2018
Elien M. Doorduijn, Marjolein Sluijter, Koen A. Marijt, Bianca J. Querido, Sjoerd H. van der Burg, Thorbald van Hall
The first identified mouse TEIPP was a C-terminal peptide of Trh4, a ceramide synthase spanning the ER membrane.8,10 The protein is ubiquitously expressed in all somatic cells, but its peptide epitope is surprisingly only presented on TAP-deficient cells.9 Antigen processing and presentation of the epitope is independent of the proteolytic enzyme complex proteasome and the TAP transporter. Instead, release of the epitope depended on intramembrane cleavage by signal peptide peptidase (SPP).10 Using a T cell receptor-transgenic (TCR tg) mouse based on a Trh4-specific CD8+ T cell clone, we previously demonstrated that these TCR tg T cells (‘LnB5 tg’) undergo normal, efficient thymic selection and are not hampered by central or peripheral tolerance,11 most likely since the Trh4 self-peptide is only MHC-I presented in TAP-deficient cells. Upon transfer of naïve LnB5T cells in wildtype, tumor-free B6 mice, cells remain naïve as expected. In contrast, transfer of LnB5 T cells to TAP-deficient mice resulted in vigorous proliferation and strong activation, especially under inflammatory conditions.11