The Militarization of Cells

Tuesday, March 29, 2016

Once every academic quarter, the UCSF Mission Bay campus takes on a new character. Normally unlocked buildings are barricaded and guarded by (mostly) men with guns.

The occasion is the University of California Regents meeting, inspiring a “proactive” response to protesters. Last week I counted a line of eight combat-ready officers marching down Owens Street. Some drive around in ATVs, lest a perpetrator seek escape in the tall grasses of Koret Quad.

Inside the offices and research laboratories of the Mission Bay campus, the mood is different. Hot-button items -- like sexual harassment policy and calls for the resignation of the UC Davis chancellor – are rarely discussed. Eyes are turned towards microscopes, programming scripts, and strict observance of CAL/OSHA protocols.

But on the smaller scale, structures of militarization resurface in fractal manner. Each cell in the human body is monitored by proteins ready to destroy that cell if deemed necessary, a process of programmed cell death called apoptosis. As discussed previously in this column, apoptosis is not just an off switch, but a strategy employed at all stages in the development of an organism, as our features and organs are shaped not just by growth but by subtraction as well.

Despite this beneficial role, our instinct is to think of apoptosis in terms of destruction, war and brutality.

The generals of apoptosis are a group of twelve proteins called the caspases. Many proteins in cell biology are named whimsically (“Sonic hedgehog”), but the caspases are labeled in regimented fashion: caspase-1, caspase-2, caspase-3…. up to caspase-12. An influential 1998 review of caspases published in Science is titled “Caspases: Enemies within.”

This reputation is overstated, but not entirely hot air. Caspases fall within a category of proteins called proteases, proteins whose job is to chop up other proteins. Many proteins in a cell are not produced until they need to be used, but caspases are always around, existing in an inactive but easily triggered “pro-caspase” state; a radio call away from activation.

Caspases appear to have many targets within the cell, but until recently, very little has been known about the exact number of targets, which targets are prioritized, and how much overlap there is between the targets of different caspases. New research from the lab of Dr. Jim Wells at UCSF is shedding light on the organization of the caspase military.

The research, co-led by Olivier Julien and Min Zhuang, was published online in PNAS on March 22nd. The study focuses on two caspases with particularly cloudy roles: caspase-2 and caspase-6. While all caspases share core features, some are tailored for initiating the activity of other caspases (a pro-caspase is turned into an active caspase by being cut, you guessed it, by another caspase), while others, the “executioner caspases,” do the dirty work of shutting a cell down. Yet other caspases appear to play less of a role in cell death, and more of a role in inflammation or development.

These roles, however, have not yet been clearly defined. Caspase-2, for instance, shares the architecture of an initiator caspase, but seems to cut at places more characteristic of an executioner caspase.

To elucidate the roles of different caspases, Julien and Zhuang’s study asked two questions about caspase-2 and caspase-6:

  1. Which proteins are cut by these caspases?
  2. How fast are these proteins cut?

Julien and Zhuang answered these two questions using an innovative method . Previously, identifying rates of caspase cutting had been mostly limited to mixing a caspase with a single purified protein and watching how quickly that protein is chopped up. But as we know, biology is messy, and in living cells a caspase may be discerning between thousands of potential targets.

This study added caspases directly to whole cells that had been opened up, but whose proteins were still initially intact. After adding the caspases, they tested the samples at different times to chart which proteins were being degraded, and how quickly.

The team found, first of all, that caspases act on many more targets than had been identified previously. Before this study, there were 37 known targets of caspase-2 and 68 known targets of caspase-6. The data here showed 235 and 871 targets, respectively.

Furthermore, there was very little overlap between the two sets of targets suggesting that caspases are highly specialized agents.

Perhaps the most interesting information came from looking at the rates of cutting. Julien and Zhuang saw that some proteins were cut up to 500 times faster than other proteins. This reflects a more intricate and ordered program of cellular destruction: high-priority targets and low-priority targets.

Like the University of California, the basic units of life do not flourish freely and blissfully, but are often tense, on edge. Decisions are made and plans are executed. Cells die and cells live.