Professor of Biochemistry & Biophysics, UNC-CH
PHD - Mt. Sinai School of Medicine(click for Full Publication List)
HONORS & AWARDS
Cellular Biochemistry: Trafficking of Proteins in the Endosomal System
We are studying an endosomal membrane protein that pursues an unusual retrograde transport pathway to the inner nuclear membrane in response to signaling events initiated at the plasma membrane. Ring Finger Protein 13 (RNF13) is a newly characterized ubiquitin ligase embedded in the membrane of multivesicular endosomes. Ubiquitin ligases attach mono- or polyubiquitin to target proteins in order to modify their stability, activity and localization. As the 3rd enzyme (E3) of the reaction that covalently attaches the 76-amino acid ubiquitin polypeptide, RNF13 determines the specificity of the modification by transiently binding to substrates.
Retrograde transport is a novel mechanism for introduction of regulatory membrane proteins to the interior of the nucleus in response to stress or signaling. The nuclear envelope has traditionally been considered to be simply a physical barrier that regulates access to the DNA in eucaryotic cells. Recent studies indicate, however, that the nuclear envelope is additionally a key component in gene transcription, chromatin silencing, genome stability and progression through the cell cycle. Pathological conditions such as muscular dystrophies, cardiomyopathies, neurodegenerative disorders and the premature aging syndrome progeria all result from perturbations in nuclear envelope proteins functioning as transcription modulating machinery. Retrotransport of RNF13 delivers the protein to the INM and positions the RING domain, which possesses the ubiquitination activity, near DNA and its regulatory proteins. RNF13 thus has the potential to modify or initiate turnover of key nuclear proteins either in the INM or in the nucleoplasm in response to signals received at the plasma membrane.
RNF13 undergoes extensive regulated proteolysis similar to that which releases fragments of the Amyloid Precursor Protein, which form the plaques in Alzheimer's patients' brains, from the endosomal membrane. At least two distinct enzymes cleave the protein near the membrane-cytoplasm junction following proteolytic removal of the lumenal domain or ectodomain of the protein. This proteolysis solubilizes the cytoplasmic tail of RNF13, allowing it to mediate ubiquitination at sites distant from the endosome. Thus this one E3 has the potential to ubiquitinate substrates on the endosome membrane, on the plasma membrane, in the cytoplasm, on the inner nuclear membrane or in the nucleoplasm.
RNF13 is a member of the PA-TM-RING family of endosomal transmembrane proteins that share a common domain structure. PA-TM-RING proteins are broadly expressed in all tissues and are evolutionarily conserved in metazoans, but they are absent in yeast, suggesting they may modulate a function unique to multicellular organisms, such as tissue development or cell-cell interaction. RNF13 has recently been implicated in neurite outgrowth, pancreatic cancer and myoblast differentiation. The mechanism by which this ubiquitin ligase achieves these diverse affects is not known. Thus, one of our key goals is to identify substrates of the E3. Our characterization of the trafficking and proteolysis of RNF13 provides the basis for elucidation of the function of the fragments or "shrapnel" of this unusual cellular "dirty bomb."
- Bocock, J. P., Carmicle, S. and Erickson, A.H. (2010) "Trafficking and proteolytic processing of RNF13, a model PA-TM-RING family endosomal membrane E3 ubiquitin ligase, FEBS. J., in press
Erickson, A.H. (2010) "PA-TM-RING proteins: a new family of endosomal membrane proteins," FEBS J., in press
- Bocock, J. P., Carmicle-Davis, S., Madamba, E. and Erickson, A.H. (2010) "Nuclear targeting of an endosomal E3 ubiquitin ligase," Traffic 11:756-766
- Bocock, J. P., Carmicle-Davis, S., Chhotani, S., Ruffolo, M., Chu, H. and Erickson, A.H. (2009) "The PA-RING protein RNF13 is an endosomal integral membrane E3 ubiquitin ligase whose RING finger domain is released to the cytoplasm by proteolysis," FEBS J., 276:1860-1877
- Bocock, J. P., Carmicle-Davis, S., Chhotani, S., Ruffolo, M., Chu, H. and Erickson, A.H. (2009) The PA-TM-RING protein RNF13 is an endosomal integral membrane E3 ubiquitin ligase whose RING finger domain is released to the cytoplasm by proteolysis. FEBS J. in press.
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