Really enjoyed presenting some of my postdoctoral work at last week’s @grk2243 Understanding Ubiquitylation conference in Würzburg. A fantastic event in a stunning location, with an incredibly friendly research community!

RT @ASBMB: In a recent study published in @jbiolchem, researchers (@BrownLabUNSW & @hudsonwilco) found that the active form of one key #cho….

It was great fun to present my PhD work and a little of my current postdoctoral project at #HypoxEU in Dresden - thanks to the organisers for an interesting and very supportive meeting (in a beautiful location too)!

Thanks also to @rob8yang and @franceslbyrne for their valuable contributions to the study (🧵4/4).

Its precise function there is still unclear - but we are confident this unusual enzyme variant will have a role to play in the many diseases associated with SQLE overexpression and overactivity (🧵3/4).

Here, we show that the truncated and constitutively active form of an oncogenic cholesterol synthesis enzyme (SM, or SQLE) accumulates in oxygen-deprived endometrial cancer tissues and is uniquely capable of moving to the surface of lipid droplets (🧵2/4).

Thrilled to have the final pieces of my PhD work with @BrownLabUNSW published in @jbiolchem - huge thanks go to @TinaBNguy for the effort to get it across the line after my departure for the UK, and also to @ximingDu for the beautiful microscopy! (🧵1/4)

I’m incredibly excited to be selected for the new Postdoctoral Research Associate role at Gonville and Caius College @Cambridge_Uni - it’s surreal to be in the place where Howard Florey and Francis Crick once studied!@CaiusCollege #postdoc #AcademicTwitter #academicchatter

Very grateful to receive a Dean’s Award for my PhD work - and a huge thanks to @BrownLabUNSW for fostering the environment in which it could happen!.

This week I started my first postdoc in the @JamesNathanLab at the University of Cambridge! It’s a long way from Australia… but I’m excited to dig into the intersections of metabolite sensing and proteasomal degradation! #sciencetwitter #academictwitter #postdoc #academicchatter

Well, my PhD journey at @BrownLabUNSW has officially come to an end and I couldn’t have asked for a more supportive team and supervisor. It‘s sad to leave after 6+ years but I’m very keen for what the future will bring! #AcademicChatter #phdchat #research @UNSWBABS

This work is the culmination of my PhD research and I couldn't be more proud! A huge thanks to my coauthors for their contributions: @isabelle_CapHat, Ellen Olzomer, @ximingDu, @drrhondafarrell, @rob8yang, @franceslbyrne, and my supervisor Andrew Brown (@BrownLabUNSW). (10/10).

The past decade has seen an explosion in reports of SM overexpression and overactivity during cancer development, and it is very possible that the truncation and permanent activation of SM during hypoxia (a hallmark of solid tumours) is a contributing factor. (9/10).

So SM activity is promoted by its own substrate - a truly elegant example of feedFOWARD regulation! This occurs even during normoxia, and is likely important for accommodating minor squalene fluctuations and controlling tissue-specific rates of cholesterol synthesis. (8/10)

Metabolic labelling assays confirmed that squalene-induced truncation of SM to its permanently active form compensates for low oxygen levels to preserve catalytic activity. This averts further squalene accumulation (which is toxic) and allows ongoing sterol synthesis. (7/10)

Secondly, SM degradation is prematurely halted, liberating the truncated variant. Remarkably, this correlates with levels of its substrate, the hydrocarbon squalene. As SM requires molecular oxygen for activity, the onset of hypoxia causes squalene to begin accumulating. (6/10)

This is a two-step process. Firstly, the targeting of SM for degradation is accelerated. This is due to a hypoxic increase in the levels of MARCHF6, the major E3 ubiquitin ligase for SM. As you can see, its knockdown abolishes SM degradation. (5/10)

Here, we show oxygen deprivation induces dramatic truncation of SM to its permanently active form, trunSM (the western blot below might be the favourite of my entire PhD). The lower the oxygen level or the longer the hypoxic duration, the greater the amount of truncation. (4/10)

But sometimes SM is incompletely degraded, creating an enzyme variant that lacks cholesterol-sensing abilities and is permanently active even under high-cholesterol conditions (see . Until now, triggers for this incomplete degradation were unknown. (3/10).

The enzyme in question is squalene monooxygenase (SM or SQLE), which has the fascinating ability to sense membrane cholesterol levels. When these rise too high, SM is degraded to prevent unnecessary cholesterol synthesis. A truly elegant example of feedback regulation!. (2/10).