There are very few actors whose presence in a film serves as a gold-plated guarantee of quality, but Catherine Keener is one. Twice nominated for Oscars, the 49-year-old brings intelligence, deadpan humour and tough-cookie sexiness to even minor roles. It is no accident that she has become a muse to America’s leading left-field directors, including Steven Soderbergh and Spike Jonze.

The British director Michael Winterbottom is the latest internationally renowned auteur to recognise Keener’s talents by casting her in his new psychological drama, Genova. It reunites Winterbottom with the French screenwriter Laurence Coriat, who previously scripted the director’s 1999 ensemble piece, Wonderland.

The film stars Colin Firth as a recently widowed father who moves with his two daughters to Italy after a family tragedy. Keener co-stars as the friend who offers comfort when the girls are haunted by spooky visions. Nicolas Roeg’s 1983 suspense classic Don’t Look Nowis an obvious reference point, but Keener is reluctant to burden Genova with labels or comparisons. “I have a hard time compartmentalising films like that,” she frowns.

“I just look at it as this story. Colin loses his wife and the children lose their mother. They come to Italy. I happen to be there as an old friend, and I try to help alleviate their pain. I can’t really say what’s inside Michael’s mind, or any film-maker’s mind.”

Keener calls Winterbottom “kind of mysterious” but raves about his eclectic body of work, singling out Jude and 24 Hour Party People. Like most Winterbottom productions, Genova was shot in a no-frills, fast-moving, docu-drama style. Hollywood-style luxuries such as private trailers were not an option, Keener says, and rightly so.

“You’re on your feet a lot,” she nods. “Michael’s very quiet but he works like a dog; he just works tirelessly, so if someone’s doing that you want to follow suit. There wasn’t a lot of room for complaining, which is good. My favourite part of this is being on set with the crew, working. Everyone’s ready to do their job, and you should be, too.”

Keener is a striking, tomboyish beauty with a nononsense reputation and a flair for feisty, sardonic character roles. If she wasn’t wearing an Obama T-shirt during our interview I might be tempted to call her the Sarah Palin of American cinema.

“I don’t want to attack Sarah Palin,” Keener frowns, “but I just think she should be questioned and challenged, like every other candidate, fairly and equally. It’s not appropriate to back off because she is perceived as ‘one of us’. I’m a feminist but I just feel there’s hesitancy on the part of women on the opposite side ideologically to challenge her, because of that notion of firing on your own troops.”

Born in Miami in 1959, Keener came to acting by a circuitous route. Her parents, Jim and Evelyn, sent her to Catholic school. The third of five children, young Catherine once even dreamt of becoming a nun.

“It definitely left its imprint on me,” she says. “I don’t even consider myself a Catholic any more, but I’ve never gone and got myself excommunicated, ha! So I guess technically I’m still one. ”

Keener dabbled in theatre acting, but never harboured serious stage ambitions. Instead, she took a job with the casting agent Gail Eisenstadt. It was Eisenstadt who convinced her young protégée to try out for film roles. She crossed the line from casting assistant to bit-part actress in the 1986 David Mamet adaptation About Last Night. A trickle of tiny TV jobs followed, including LA Law and Seinfeld.

But it was the New York director Tom DiCillo who really put Keener on the indie-movie map, casting her alongside a young Brad Pitt in his 1991 comedy Johnny Suede. During her audition, she threw a shoe at Pitt, reportedly scarring his leg for life. “I just threw a lame ball, with a shoe,” she laughs. “But no, he doesn’t have a scar. Maybe psychologically he does. But I can dream, can’t I?”

She remains friends with Pitt despite the incident, and despite co-starring in DiCillo’s next film, Living in Oblivion, which featured a pompous young movie hunk clearly modelled on His Bradness. But it was another fruitful working friendship, with the director Spike Jonze and screenwriter Charlie Kaufman, that brought her to mainstream attention with Being John Malkovich in 1999.

Casting Keener as a rapaciously sexy femme fatale, and Cameron Diaz as her dowdy love rival, was an inspired antiHollywood move by Jonze. “I thought I’d never get that job,” she says. “I was insecure about it; I didn’t think he’d cast me right. But that’s Spike – he flips things. It worked in that case because the whole movie was upside down.”

Keener is surely being modest here. She is, after all, the thinking film fan’s sex symbol. “God no!” she splutters. “I don’t know how to respond to that. Do I just say yes . . .?”

It is a journalistic cliché to describe more credible film stars as reluctant celebrities, but Keener has certainly avoided gossip columns and high-profile media exposure during a career spanning more than two decades. She guards her private life closely. She was married to fellow actor Dermot Mulroney for 17 years, and they had a son in 1999, but later separated and divorced last year. Raising the subject of her love life, I am expecting a firm rebuttal. She does not disappoint.

“Go f*** yourself,” Keener says, hooting with laughter. I persist, bringing up recent rumours that she is romancing the actor Benicio Del Toro. She just scoffs incredulously. “What? No, I don’t want to tell you anything, even if they are stupid lies.” It speaks volumes about Keener’s nose for quality roles that there is barely a single dud in her dozens of credits. She even emerged from lowbrow comedies, such as Judd Apatow’s The 40-Year-Old-Virgin and Steve Coogan’s latest Hollywood venture Hamlet 2, with her credibility intact. Constantly in demand, her strategy of favouring more independent, low-to-mid budget productions seems to be paying off.

Keener’s work rate is impressive. She can also be seen soon in Barry Levinson’s comedy What Just Happened? Next year she co-stars in half a dozen major releases, including Joe Wright’s The Soloist and Spike Jonze’s Where The Wild Things Are, and is in Charlie Kaufman’s directing debut, Synecdoche, New York, also in this year’s LFF. At her age, Keener is bucking the notorious unspoken Hollywood rule that actresses pass their sell-by date at 40.

“I don’t see a lot of parts for people like me, so I guess that’s still true,” she ponders. “But I think it’s getting better. The glass is way more than half full. Life’s been really, really good to me.”

Genova shows at OWE2, Oct 22, 8.30pm and OWE1, Oct 26, 4pm

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