Jonathan H. Lin, M.D., Ph.D.
Assistant Professor
Pathology, Cellular and Molecular Medicine
jlin@ucsd.edu
Phone: (858) 534-2743
FAX: (858)534-4715 Web Page

Biography:
Assistant Professor - Department of Pathology
Assistant Adjunct Professor - Department of Cellular and Molecular
Medicine

Research:
CELLULAR RESPONSES TO PROTEIN MISFOLDING

Organism health depends on the accuracy of the signals sent and
received by constituent cells. Proteins, either secreted from the
cell or embedded in the plasma membrane to monitor the environment,
transmit much of this information. On the basis of these signals,
cells make vital decisions – when and where to divide, migrate or
change shape, differentiate, or die. Cells have evolved elaborate
mechanisms to ensure the accuracy with which proteins are folded and
assembled before export or transport to the cell surface. Stringent
quality control is imposed by the endoplasmic reticulum (ER), a
membrane-bound labyrinth of tubes and sacs, where virtually all plasma
membrane and secreted proteins begin their journey to the surface.
Only properly folded proteins are allowed to leave the ER; misfolded
proteins are degraded. In this way, cells display or release only
high-quality, functional proteins.

To maintain fidelity, the cell needs to fold proteins as they are
made, and this system needs to adapt to changing environmental
conditions. This feat is achieved by a set of intracellular signaling
pathways, collectively termed the “unfolded protein response” (UPR),
which sense when the ER has accumulated too many misfolded proteins
and in turn, activate transcription of certain genes that enhance the
ER’s protein folding capacity as needed. UPR signaling can protect
cells from ER stress by expanding the amount of ER in the cell,
enhancing the degradation of misfolded proteins, and reducing the
synthesis of new proteins. But if homeostasis cannot be
reestablished, UPR signaling induces cell death by apoptosis, an
effective means of protecting the organism from rogue cells expressing
dysfunctional or even toxic signaling molecules. Our research focuses
on two themes: 1) understanding the molecular mechanisms by which UPR
signaling protects cells or alternatively promotes cell death and 2)
investigating the role of UPR signaling in the pathogenesis of human
diseases associated with protein misfolding.

Characterize the molecular mechanisms of UPR signaling

The molecular gatekeepers of the UPR are ER-resident transmembrane
proteins with luminal domains that monitor the quality of protein
folding in the ER coupled across the ER membrane to cytosolic effector
domains that transmit that information to the rest of the cell. IRE1
and PERK independently govern two key UPR signal transduction
pathways. Protein misfolding concomitantly activates IRE1 and PERK,
thereby obscuring insight into protective or proapoptotic
contributions of these two signaling pathways toward life or death
cell fates. We created artificial forms of IRE1 and PERK whose
activities could be activated by application of cell permeable small
molecules such as the ATP analog, 1NM-PP1, or the FK506 derivative,
AP20187. We created isogenic human cell lines bearing these
chemically sensitized alleles, which allowed us to selectively
activate IRE1 or PERK signaling independent of protein misfolding.
Using this strategy, we demonstrated that IRE1 signaling promoted cell
survival but surprisingly, this signaling pathway was specifically
shut down by persistent ER stress. By contrast, we demonstrated that
sustained PERK signaling directly impaired cell viability by
inhibiting proliferation and promoting apoptosis. These findings
provide a molecular basis to investigate how UPR signaling promotes
cell survival or cell death in response to protein misfolding. These
findings raise new questions that we are currently studying such as:
How does sustained IRE1 signaling promote cell health? How does
sustained PERK signaling lead to cell death?

Characterize the role of UPR signaling in protein folding diseases

Protein misfolding occurs in numerous human diseases including cancer,
diabetes, neurodegeneration, and viral infections. Rhodopsin is a
membrane protein specifically expressed by photoreceptor neurons in
the eye. Rhodopsin folds and matures in the ER before export to the
photoreceptor outer segment where it functions as a light sensor.
Mutations in rhodopsin underlie many forms of retinitis pigmentosa, a
disease in which photoreceptor cells die ultimately leading to
blindness for the individual. The most common form of heritable
retinitis pigmentosa in people arises from a proline to histidine
mutation at amino acid 23 (P23H) in rhodopsin. P23H rhodopsin is
misfolded and retained in the ER. Photoreceptors expressing P23H
rhodopsin eventually die leading to blindness. In collaboration with
the laboratory of Matt LaVail, we have examined transgenic animal
models of retinitis pigmentosa in which P23H rhodopsin expression in
photoreceptors leads to death of the photoreceptor cells and
organismal blindness. We have demonstrated that UPR signaling
pathways are abnormally dysregulated in the retinas of animals
expressing P23H rhodopsin. We are using and developing genetic,
chemical-genetic, and pharmacologic tools to manipulate specific UPR
signaling pathways. We are evaluating the effects of activation or
inhibition of individual UPR signaling pathways on the onset and
progression of retinal degeneration in animals expressing misfolded
rhodopsin. These approaches are broadly applicable to other diseases
associated with ER stress and protein misfolding being studied in the
lab, including Cystic Fibrosis and certain cancers.

Publications