Modulation of deregulated chaperone-mediated autophagy by a phosphopeptide

Christophe Macri, Fengjuan Wang, Inmaculada Tasset, Nicolas Schall, Nicolas Page, Jean Paul Briand, Ana Maria Cuervo, Sylviane Muller

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The P140 peptide, a 21-mer linear peptide (sequence 131–151) generated from the spliceosomal SNRNP70/U1–70K protein, contains a phosphoserine residue at position 140. It significantly ameliorates clinical manifestations in autoimmune patients with systemic lupus erythematosus and enhances survival in MRL/lpr lupus-prone mice. Previous studies showed that after P140 treatment, there is an accumulation of autophagy markers sequestosome 1/p62 and MAP1LC3-II in MRL/lpr B cells, consistent with a downregulation of autophagic flux. We now identify chaperone-mediated autophagy (CMA) as a target of P140 and demonstrate that its inhibitory effect on CMA is likely tied to its ability to alter the composition of HSPA8/HSC70 heterocomplexes. As in the case of HSPA8, expression of the limiting CMA component LAMP2A, which is increased in MRL/lpr B cells, is downregulated after P140 treatment. We also show that P140, but not the unphosphorylated peptide, uses the clathrin-dependent endo-lysosomal pathway to enter into MRL/lpr B lymphocytes and accumulates in the lysosomal lumen where it may directly hamper lysosomal HSPA8 chaperoning functions, and also destabilize LAMP2A in lysosomes as a result of its effect on HSP90AA1. This dual effect may interfere with the endogenous autoantigen processing and loading to major histocompatibility complex class II molecules and as a consequence, lead to lower activation of autoreactive T cells. These results shed light on mechanisms by which P140 can modulate lupus disease and exert its tolerogenic activity in patients. The unique selective inhibitory effect of the P140 peptide on CMA may be harnessed in other pathological conditions in which reduction of CMA activity would be desired.

Original languageEnglish (US)
Pages (from-to)472-486
Number of pages15
JournalAutophagy
Volume11
Issue number3
DOIs
StatePublished - Jan 1 2015

Fingerprint

Phosphopeptides
Autophagy
B-Lymphocytes
Down-Regulation
Phosphoserine
Clathrin
Peptides
Autoantigens
Lysosomes
Major Histocompatibility Complex
Systemic Lupus Erythematosus
T-Lymphocytes
Survival
Therapeutics
Proteins

Keywords

  • Antigen-presenting cells
  • Autophagy
  • B lymphocytes
  • Chaperone-mediated autophagy
  • Class II MHC molecules
  • Heat shock proteins
  • HSPA8/HSC70
  • Lupus
  • Lysosomal chaperones
  • Lysosomes

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Macri, C., Wang, F., Tasset, I., Schall, N., Page, N., Briand, J. P., ... Muller, S. (2015). Modulation of deregulated chaperone-mediated autophagy by a phosphopeptide. Autophagy, 11(3), 472-486. https://doi.org/10.1080/15548627.2015.1017179

Modulation of deregulated chaperone-mediated autophagy by a phosphopeptide. / Macri, Christophe; Wang, Fengjuan; Tasset, Inmaculada; Schall, Nicolas; Page, Nicolas; Briand, Jean Paul; Cuervo, Ana Maria; Muller, Sylviane.

In: Autophagy, Vol. 11, No. 3, 01.01.2015, p. 472-486.

Research output: Contribution to journalArticle

Macri, C, Wang, F, Tasset, I, Schall, N, Page, N, Briand, JP, Cuervo, AM & Muller, S 2015, 'Modulation of deregulated chaperone-mediated autophagy by a phosphopeptide', Autophagy, vol. 11, no. 3, pp. 472-486. https://doi.org/10.1080/15548627.2015.1017179
Macri, Christophe ; Wang, Fengjuan ; Tasset, Inmaculada ; Schall, Nicolas ; Page, Nicolas ; Briand, Jean Paul ; Cuervo, Ana Maria ; Muller, Sylviane. / Modulation of deregulated chaperone-mediated autophagy by a phosphopeptide. In: Autophagy. 2015 ; Vol. 11, No. 3. pp. 472-486.
@article{0edb72edddf9411c9328306fc88a74e9,
title = "Modulation of deregulated chaperone-mediated autophagy by a phosphopeptide",
abstract = "The P140 peptide, a 21-mer linear peptide (sequence 131–151) generated from the spliceosomal SNRNP70/U1–70K protein, contains a phosphoserine residue at position 140. It significantly ameliorates clinical manifestations in autoimmune patients with systemic lupus erythematosus and enhances survival in MRL/lpr lupus-prone mice. Previous studies showed that after P140 treatment, there is an accumulation of autophagy markers sequestosome 1/p62 and MAP1LC3-II in MRL/lpr B cells, consistent with a downregulation of autophagic flux. We now identify chaperone-mediated autophagy (CMA) as a target of P140 and demonstrate that its inhibitory effect on CMA is likely tied to its ability to alter the composition of HSPA8/HSC70 heterocomplexes. As in the case of HSPA8, expression of the limiting CMA component LAMP2A, which is increased in MRL/lpr B cells, is downregulated after P140 treatment. We also show that P140, but not the unphosphorylated peptide, uses the clathrin-dependent endo-lysosomal pathway to enter into MRL/lpr B lymphocytes and accumulates in the lysosomal lumen where it may directly hamper lysosomal HSPA8 chaperoning functions, and also destabilize LAMP2A in lysosomes as a result of its effect on HSP90AA1. This dual effect may interfere with the endogenous autoantigen processing and loading to major histocompatibility complex class II molecules and as a consequence, lead to lower activation of autoreactive T cells. These results shed light on mechanisms by which P140 can modulate lupus disease and exert its tolerogenic activity in patients. The unique selective inhibitory effect of the P140 peptide on CMA may be harnessed in other pathological conditions in which reduction of CMA activity would be desired.",
keywords = "Antigen-presenting cells, Autophagy, B lymphocytes, Chaperone-mediated autophagy, Class II MHC molecules, Heat shock proteins, HSPA8/HSC70, Lupus, Lysosomal chaperones, Lysosomes",
author = "Christophe Macri and Fengjuan Wang and Inmaculada Tasset and Nicolas Schall and Nicolas Page and Briand, {Jean Paul} and Cuervo, {Ana Maria} and Sylviane Muller",
year = "2015",
month = "1",
day = "1",
doi = "10.1080/15548627.2015.1017179",
language = "English (US)",
volume = "11",
pages = "472--486",
journal = "Autophagy",
issn = "1554-8627",
publisher = "Landes Bioscience",
number = "3",

}

TY - JOUR

T1 - Modulation of deregulated chaperone-mediated autophagy by a phosphopeptide

AU - Macri, Christophe

AU - Wang, Fengjuan

AU - Tasset, Inmaculada

AU - Schall, Nicolas

AU - Page, Nicolas

AU - Briand, Jean Paul

AU - Cuervo, Ana Maria

AU - Muller, Sylviane

PY - 2015/1/1

Y1 - 2015/1/1

N2 - The P140 peptide, a 21-mer linear peptide (sequence 131–151) generated from the spliceosomal SNRNP70/U1–70K protein, contains a phosphoserine residue at position 140. It significantly ameliorates clinical manifestations in autoimmune patients with systemic lupus erythematosus and enhances survival in MRL/lpr lupus-prone mice. Previous studies showed that after P140 treatment, there is an accumulation of autophagy markers sequestosome 1/p62 and MAP1LC3-II in MRL/lpr B cells, consistent with a downregulation of autophagic flux. We now identify chaperone-mediated autophagy (CMA) as a target of P140 and demonstrate that its inhibitory effect on CMA is likely tied to its ability to alter the composition of HSPA8/HSC70 heterocomplexes. As in the case of HSPA8, expression of the limiting CMA component LAMP2A, which is increased in MRL/lpr B cells, is downregulated after P140 treatment. We also show that P140, but not the unphosphorylated peptide, uses the clathrin-dependent endo-lysosomal pathway to enter into MRL/lpr B lymphocytes and accumulates in the lysosomal lumen where it may directly hamper lysosomal HSPA8 chaperoning functions, and also destabilize LAMP2A in lysosomes as a result of its effect on HSP90AA1. This dual effect may interfere with the endogenous autoantigen processing and loading to major histocompatibility complex class II molecules and as a consequence, lead to lower activation of autoreactive T cells. These results shed light on mechanisms by which P140 can modulate lupus disease and exert its tolerogenic activity in patients. The unique selective inhibitory effect of the P140 peptide on CMA may be harnessed in other pathological conditions in which reduction of CMA activity would be desired.

AB - The P140 peptide, a 21-mer linear peptide (sequence 131–151) generated from the spliceosomal SNRNP70/U1–70K protein, contains a phosphoserine residue at position 140. It significantly ameliorates clinical manifestations in autoimmune patients with systemic lupus erythematosus and enhances survival in MRL/lpr lupus-prone mice. Previous studies showed that after P140 treatment, there is an accumulation of autophagy markers sequestosome 1/p62 and MAP1LC3-II in MRL/lpr B cells, consistent with a downregulation of autophagic flux. We now identify chaperone-mediated autophagy (CMA) as a target of P140 and demonstrate that its inhibitory effect on CMA is likely tied to its ability to alter the composition of HSPA8/HSC70 heterocomplexes. As in the case of HSPA8, expression of the limiting CMA component LAMP2A, which is increased in MRL/lpr B cells, is downregulated after P140 treatment. We also show that P140, but not the unphosphorylated peptide, uses the clathrin-dependent endo-lysosomal pathway to enter into MRL/lpr B lymphocytes and accumulates in the lysosomal lumen where it may directly hamper lysosomal HSPA8 chaperoning functions, and also destabilize LAMP2A in lysosomes as a result of its effect on HSP90AA1. This dual effect may interfere with the endogenous autoantigen processing and loading to major histocompatibility complex class II molecules and as a consequence, lead to lower activation of autoreactive T cells. These results shed light on mechanisms by which P140 can modulate lupus disease and exert its tolerogenic activity in patients. The unique selective inhibitory effect of the P140 peptide on CMA may be harnessed in other pathological conditions in which reduction of CMA activity would be desired.

KW - Antigen-presenting cells

KW - Autophagy

KW - B lymphocytes

KW - Chaperone-mediated autophagy

KW - Class II MHC molecules

KW - Heat shock proteins

KW - HSPA8/HSC70

KW - Lupus

KW - Lysosomal chaperones

KW - Lysosomes

UR - http://www.scopus.com/inward/record.url?scp=84934278332&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84934278332&partnerID=8YFLogxK

U2 - 10.1080/15548627.2015.1017179

DO - 10.1080/15548627.2015.1017179

M3 - Article

VL - 11

SP - 472

EP - 486

JO - Autophagy

JF - Autophagy

SN - 1554-8627

IS - 3

ER -