The
Nicchitta lab studies the role of the endoplasmic reticulum (ER)
in the regulation of mRNA partitioning, trafficking and localization
in the cell. We hypothesize that the ER serves a previously unappreciated
role in the translation and sorting of newly transcribed and exported
mRNAs. In this model, newly exported mRNAs are translated on ER-bound
ribosomes, with this initial round
of translation playing a critical role in directing the sorting of
the mRNA between the cytosol and the ER compartments. In addition,
we have reported that some mRNAs, encoding cytosolic proteins, are
partitioned to, and translated on ER-bound ribosomes. These findings
suggest new roles for the ER in partitioning and localization of
mRNAs and proteins in the cell.
Lerner et al. (2003) RNA (Sept) 9: 1123-1137 -PDF-
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1: Protein synthesis on the endoplasmic reticulum. Cytosolic ribosomes
engaged in the synthesis of secretory or membrane proteins
are recognized early in synthesis and targeted via the SRP pathway
to the ER membrane. At the ER, the signal sequence engages the
protein-conducting channel and protein translocation ensues.
As illustrated, the termination of protein synthesis results
in the release of ribosomal subunits from the ER membrane to
the cytosol. |
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2. A model identifying the endoplasmic reticulum as a platform
for mRNA sorting and localization. In this model, newly transcribed
mRNAs exit the nuclear pore complex and undergo translation on ER-bound
ribosomes. If the mRNA encodes a cytosolic protein, it is released
to the cytosol during translation in a process termed “elongation-coupled
ribosome release (E-CRR). If the mRNA encodes a secretory or membrane
protein, it remains associated with the ER. We also postulate that
some mRNAs assemble into complexes with motor/adaptor proteins on the
ER, to undergo localization to distal compartments of the cell. |
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Figure
3: Single cell in situ mRNA hybridization analysis of mRNA distribution. mRNAs
encoding cytosolic proteins can be partitioned to the ER. Single
cell in situ hybridization analyses were performed to identify
the steady-state distribution of mRNAS encoding GRP94 (top panel),
GAPDH (middle panel) or Hsp90 (bottom panel). Whereas mRNAs encoding
GRP94 and GAPDH display their expected distribution, mRNAs encoding
Hsp90 are “non-canonically” enriched on the ER. The
mechanism of such enrichment is under investigation. Panels on
the far right represent 3-D renderings of mRNA distribution, as
determined in Image J. |
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