Compositions and methods for modulating NCOA4-mediated autophagic targeting of ferritin
Described herein are methods of modulating autophagic targeting of ferritin in a cell, wherein the method comprises modulating the level and/or activity of nuclear receptor coactivator 4 (NCOA4) in the cell. Also provided are related methods of treatment.
1. A method of decreasing binding between nuclear receptor coactivator 4 (NCOA4) and ferritin heavy chain (FTH1) in a cell, wherein the method comprises delivering to the interior of a cell comprising NCOA4 and FTH1 an agent that decreases the binding between the C-terminus of NCOA4 and FTH1, wherein the C-terminus of NCOA4 consists of amino acids 235-614 of SEQ ID NO: 4, and
wherein the agent is selected from the group consisting of:
(a) an inhibitory NCOA4-specific antibody,
(b) an inhibitory FTH1-specific antibody,
(c) a NCOA4-specific intrabody,
(d) a dominant negative NCOA4,
(e) a peptide fragment of NCOA4 comprising an amino acid sequence set forth in SEQ ID NO: 11 with 0 to 3 amino acid substitutions, and
(f) a peptide fragment of FTH1 comprising an amino acid sequence selected from the group consisting of: amino acids 16-34 of SEQ ID NO: 6 with 0 to 3 amino acid substitutions, amino acids 103-125 of SEQ ID NO: 6 with 0 to 3 amino acid substitutions, and amino acids 78-88 of SEQ ID NO: 6 with 0 to 3 amino acid substitutions.
2. The method of claim 1 , wherein the agent is a peptide fragment of NCOA4 comprising an amino acid sequence set forth in SEQ ID NO: 11 with 0 to 3 amino acid substitutions.
3. The method of claim 2 , wherein the peptide fragment comprises the amino acid sequence of
SEQ ID NO: 1 (SRIADSFQVIKNSPLSEWLIRPPYKEGSPK) or
SEQ ID NO: 11 (SFQVIKNSPLSEWLIRPPYKEGSPK).
4. The method of claim 2 , wherein the peptide fragment consists of the amino acid sequence of
SEQ ID NO: 1 (SRIADSFQVIKNSPLSEWLIRPPYKEGSPK).
5. The method of claim 2 , wherein the peptide fragment consists of the amino acid sequence of
SEQ ID NO: 11 (SFQVIKNSPLSEWLIRPPYKEGSPK).
6. The method of claim 1 , wherein the agent is a peptide fragment of FTH1 comprising amino acids 16-34 of SEQ ID NO: 6 with 0 to 3 amino acid substitutions.
7. The method of claim 1 , wherein the agent is a peptide fragment of FTH1 comprising amino acids 103-125 of SEQ ID NO: 6 with 0 to 3 amino acid substitutions.
8. The method of claim 1 , wherein the agent is a peptide fragment of FTH1 comprising amino acids 78-88 of SEQ ID NO: 6 with 0 to 3 amino acid substitutions.