TMEM184: Scientists Find the Long-Sought Lysosome Calcium Uptake Transporter

Back in 1991, scientists saw that lysosomes, tiny compartments inside our cells, soak up calcium. What nobody could find was the protein doing the soaking. This week, Haoxing Xu's team at Zhejiang University School of Medicine and the Liangzhu Laboratory named it in Science: a pair of membrane proteins called TMEM184B and TMEM184C, which the team calls lysosomal calcium transporters, or LyCaTs.

In textbooks, the lysosome is the cell's garbage disposal, an acidic bubble full of digestive enzymes that breaks down worn-out parts. Over the past decade, researchers have learned it is also a signaling hub involved in sensing nutrients, recycling and patching damaged membranes. Calcium is one of the main signals tying that work together, just as it drives muscle contraction, heartbeats and nerve signals elsewhere in the body.

Lysosomes are among the cell's richest calcium stores. How calcium gets out was settled in 2007, when Xu's group identified the release channel TRPML1. But every store needs a way to refill, and the way in was the missing piece.

The team's approach was brute force. They built a library of lysosomal membrane proteins, knocked out candidates one by one with gene editing and used calcium imaging to check whether lysosomes could still take up calcium. According to Zhejiang University, co-first author Weijie Cai was more than 60 proteins in with nothing to show for it. Somewhere in the 70s or 80s, a clear uptake defect finally appeared. He had a labmate repeat the experiment blind before reporting it, and the result held. From the start of screening in 2023 to publication took more than three years.

What's new goes beyond finding the protein. The field had generally assumed lysosomes pull in calcium by trading it for hydrogen ions, using the acid inside. TMEM184 doesn't need the acid and doesn't burn energy. Instead it relies on a neighbor. When a lysosome runs low, the endoplasmic reticulum, the cell's biggest calcium reservoir, releases calcium right where the two compartments touch. That creates a small high-calcium patch, and TMEM184 lets the calcium flow into the lysosome.

Think of a warehouse built right next to a water tower. The warehouse can't pump water uphill on its own, but when the tower opens a valve at the door, water runs straight in. The paper also shows TMEM184 is picky: it moves calcium while keeping out single-charge ions like sodium and potassium.

Why it matters beyond the lab: without TMEM184B and TMEM184C, lysosomal calcium stores ran dry, calcium release weakened, and the lysosome's ability to secrete, renew itself and repair its membrane broke down, mirroring what happens when the TRPML1 exit channel is missing. Earlier studies had found TMEM184B mutations in people with a neurodevelopmental disorder, but no one knew how they caused disease. This study shows such a mutation wrecks calcium transport, and mice lacking Tmem184b developed severe motor problems. That gives researchers studying some rare diseases a concrete mechanism, and a specific target to aim at in future work.

Original source published: Science, Nov 13, 2026 Beijing time / Nov 12, 2026 US Eastern time