# Noncanonical roles of Bim in heat shock-induced cell death

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $490,122

## Abstract

PROJECT SUMMARY/ABSTRACT
Severe hyperthermia (heatstroke) is due to a failure of thermoregulation that can lead to cell death in various
tissues resulting in multisystem organ failure. Hyperthermia generally results from overexertion due to severe
physical activity and/or prolonged exposure to elevated temperatures. Patients who suffer from anhidrosis or
hypohidrosis, due to disease or certain medications, such as anesthetics, diuretics, anticholinergics, and
amphetamines, are likewise at greater risk. Apart from the negative effects of hyperthermia, in the clinic a variety
of approaches are being utilized to induce localized hyperthermia in the treatment of various cancers, as many
tumors exhibit enhanced sensitivity to heat. Despite the general importance of heat shock responses, however,
the mechanisms by which heat induces cell death remain unclear. Heat shock reportedly induces cell death
through the activation of various canonical pathways involving the initiator caspases-2, -8, and -9; however, we
and others find that while these pathways can serve to amplify the cell death signal, they are largely dispensable
for heat shock-induced cell death, particularly at higher temperatures or following longer exposures. Instead, in
a surprising discovery, we have found that Bim mediates heat shock-induced cell death, independently of its
BH3 domain, through an interaction with the LC8 dynein light chain subunit of the dynein motor complex (DMC).
In binding to LC8, Bim promotes anterograde trafficking of lysosomes from the perinuclear region to the cell
periphery, where they become sensitive to the effects of heat shock. Additional data indicate that peripheral
lysosomes undergo direct membrane permeabilization (LMP) or exocytotic release following heat shock,
resulting in the release of cathepsins into the cytoplasm or extracellular space, respectively. Moreover, knockout
or depletion of cathepsin L (CatL) renders cells highly resistant to cell death. Lastly, while cathepsins released
into different cellular compartments play roles in mediating cell death, targeted localization of the cathepsin
inhibitor, cystatin B (CSTB), to the nucleus results in profound suppression of heat shock-induced cell death.
Thus, our overall hypothesis is that Bim plays a critical noncanonical role in regulating lysosomal number and
positioning within cells, and as a result, it determines the susceptibility of peripheral lysosomes to heat shock-
induced LMP/exocytosis, cathepsin release, and cell death. In four specific aims, we will determine: (1) the roles
of Bim in lysosome number and positioning; (2) the roles of Bim in heat shock-induced LMP and lysosome
exocytosis; (3) the roles of nuclear CatL in heat shock-induced cell death; and (4) the roles of Bim in two mouse
models of localized and whole-body hyperthermia. Collectively, the proposed studies will provide important
insights into an unexpected role for Bim in regulating lysosomal trafficking with far reaching ...

## Key facts

- **NIH application ID:** 10941731
- **Project number:** 1R01GM155335-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Shawn B Bratton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $490,122
- **Award type:** 1
- **Project period:** 2024-08-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10941731

## Citation

> US National Institutes of Health, RePORTER application 10941731, Noncanonical roles of Bim in heat shock-induced cell death (1R01GM155335-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10941731. Licensed CC0.

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