Bacterial cells form molecules “Hunger Games” to defeat virus invaders

On the invisible battlefield of microscopic life, bacteria have evolved amazing weapons to resist viral predators. Now, scientists have discovered one of the most elegant defense capabilities to date, a network of launching proteins for starving invaders by depleting key cellular resources.

Imagine a microscopic siege. The virus violates bacterial defenses and begins hijacking the cells’ machinery. But instead of surrendering, the bacterial cells fired their own counterattack: filamentous protein networks, which methodically dismantle NAD+, a molecule essential for cellular function as fuel, and is the automotive engine.

This newly discovered protein, called CAT1, creates delicate molecular structures that fundamentally change the battlefield of infection. The results were published scientifically by researchers at Rockefeller University and Memorial Sloan Kettering Cancer Center yesterday.

“The collective work in our lab reveals the effectiveness and different roles of these Kraft effectors,” said Luciano Marraffini of Rockefeller Bacteriology Laboratory, who co-led the study. “Their range of molecular activity is amazing.”

Beyond genetic scissors

Now, most people associate CRISPR with the Nobel Prize-winning gene editing technology in 2020. But this is just human adaptation to the ancient bacterial immune system.

Although CRISPR-CAS9’s reputation stems from its ability to accurately cut DNA, bacteria have far more defense strategies than our technology applications have shown.

CAT1 belongs to a family of proteins called CARF effectors that do not directly attack viral DNA. Instead, they transform the infected cells themselves into hostile areas for viral replication, which is actually a coking Earth defense strategy at the molecular level.

The difference between CAT1 is that its target: nicotinamide adenine dinucleotide (NAD+), a molecule at the center of cell metabolism. By cleaving NAD+, CAT1 essentially pulls the metabolic emergency brake onto the cells.

“Once a sufficient amount of NAD+ is cut into enough NAD+, the cell enters a growing state,” explains Christian Baca, a graduate student at Marraffini Lab, co-first author of the study. “With the suspension of cellular function, the phages no longer spread and spread to other bacterial populations. In this way, CAT1 is similar to CAM1 and CAD1 because they both provide population-level bacterial immunity.”

Nano-scale architectural miracle

The team revealed the unexpectedly complex architecture of CAT1, using cryo-electron microscopy, a technology that allows scientists to visualize molecular structures through flickering freezes. They found that this was significant – a protein that aggregated into a network similar to microscopic scaffolding.

These are not random formations. When bacterial cells detect viral infection, the CAT1 protein organizes itself into precise geometric patterns, enhancing its metabolite degradation ability.

Co-first author Puja Majumder is a postdoctoral research scholar in the lab of Dinshaw Patel at Memorial Sloan Kettering Cancer Center, who was shocked by the complexity. “The filaments interact with each other to form triangular helical bundles, which can then be expanded to form pentagonal helical bundles,” she explained.

The process is similar to the molecular origami-folding and assembly of protein components into complex three-dimensional structures with specific functions. When researchers destroyed this building through genetic mutations, CAT1’s protective ability was greatly reduced.

Molecular Alert System

How do bacterial cells know when to deploy this defense? The answer lies in a molecular alert system that rivals our most complex surveillance technologies.

When the CRISPR components detect viral genetic material in the cell, they trigger the production of cyclic quadrilaterals – acrylate (CA4) – which can be used as a small signal molecule that acts as a wake-up bell and activation bond.

These CA4 molecules bind to CAT1 proteins, such as molecular glues, to enable them to assemble into defensive formations. The researchers’ structural analysis revealed the framework for the construction of the entire filament network by sandwiching the CA4 molecules between protein domains.

This signal-dependent component ensures that CAT1 remains inactive until needed to prevent false alarms that unnecessarily disrupt cellular metabolism.

Altruistic defense strategy

This study elucidates an attractive aspect of bacterial immunity—a form of cellular altruism in which infected cells sacrifice their direct growth, thus growing for the greater benefit of bacterial populations.

Unlike our immune cells that specifically target and eliminate threats while retaining themselves, bacteria that adopt CAT1 essentially put themselves in a state of stagnation. Time-lapse microscopy shows that when Cat1 is activated in bacterial cultures of infected phages, infected cells stop growing, while uninfected neighbors continue to flourish.

It is worth noting that bacteria that activate CAT1 do not necessarily die. If the trigger signal fades, these cells can restore normal function, as NAD+ levels restore a cell to hibernation rather than suicide.

Expanding defensive tracks

CAT1 has added more and more subdirectories of CARF effect through different protection mechanisms. Some of the previous findings by these teams include bringing cell membranes or flooded proteins with toxic molecules to prevent virus replication.

A particularly interesting aspect of CAT1 is its self-sufficiency. “Usually in the Type III CRISPR system, you have two activities that contribute to the immune effect,” Baca notes. “However, most bacteria that encode CAT1 appear to rely primarily on CAT1 to obtain their immune effect.”

This independence suggests that NAD+ depletion is a particularly effective antiviral strategy, perhaps cutting off the supply line to starve a molecule that invades an invading army.

Evolutionary meaning

As scientists continue to map the various immune strategies employed in the microbial world, each discovery gives a glimpse of the evolutionary weapon race between bacteria and their viral predators.

“Although I think we’ve proven the big picture – the Kraft effector is very good at preventing phage replication, we still have a lot of details about how they do it.

These molecular warfares have been launched for billions of years under our notice, and have produced sophisticated defense systems that now give us some insight into our understanding of immunity and may inspire new biotech applications. In the micro arena where bacteria and virus competition, strategies such as CAT1 resource depletion show that sometimes the most effective defense is not direct attacks, but completely changing the rules of participation.