Session Type: Abstract Submissions (ACR)
Background/Purpose: In the pipeline of molecules with a potential for treating lupus patients, the P140 peptide/Lupuzor holds a lot of promise. P140 is a 21-mer linear peptide (sequence 131-151) that is derived from the small nuclear ribonucleoprotein U1-70K and that is phosphorylated at the Ser140position. In a multicenter, randomized, placebo-controlled phase IIb study, Lupuzor was safe and met its primary efficacy end points in lupus patients (Zimmer et al., 2012). These results confirm data generated in MRL/lpr lupus-prone mice in which the preclinical studies were performed. The mechanism of action of P140 was further studied in this mouse model.
Methods: Immunocytochemical analyses were used to identify the way of P140 entry into B cells, and CMA activity was assessed in fibroblasts stably expressing a photoactivable CMA reporter. FACS analyses after LysoTracker and LysoSensor staining of isolated B cells were used to study the number and acidity of lysosomes in B cells from MRL/lpr mice.
Results: We found previously that P140 reduces autophagic flux in MRL/lpr B cells (Page et al., 2011) and that macroautophagy (the best characterized type of autophagy) is abnormally enhanced in T lymphocytes from lupus mice and patients (Gros et al., 2012). In this work, we show that a selective form of autophagy, chaperone-mediated autophagy (CMA), is a key target of P140 and demonstrate that the P140 inhibitory effect on CMA results from its ability to alter the integrity of the HSC70/hsp90 heterocomplex of lysosomal chaperones. Expression of HSC70 and LAMP-2A, the two main CMA components, which is increased in MRL/lpr B cells, is down-regulated after P140 treatment. P140 enters MRL/lpr B lymphocytes via a clathrin-dependent endo-lysosomal pathway and accumulates at the lysosomal lumen. There, it may act both by directly hampering HSC70 chaperoning functions and, as a result of loss of hsp90 function, by destabilizing LAMP-2A in lysosomes. This dual effect may interfere with the endogenous (auto)antigen processing and loading to MHCII molecules and as a consequence, lower activation of autoreactive T cells.
Conclusion: Our findings provide the first demonstration showing that P140 peptide acts directly on CMA. These results shed light on mechanisms by which P140 can modulate lupus disease and by which it may operate in humans affected by this disorder.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/chaperone-mediated-autophagy-as-a-target-of-therapeutic-p140-peptide-used-in-lupus/